chr13-50945445-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4
The NM_024570.4(RNASEH2B):c.529G>A(p.Ala177Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,612,756 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_024570.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00145 AC: 221AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00140 AC: 351AN: 251300Hom.: 0 AF XY: 0.00158 AC XY: 214AN XY: 135820
GnomAD4 exome AF: 0.00208 AC: 3031AN: 1460468Hom.: 5 Cov.: 30 AF XY: 0.00206 AC XY: 1499AN XY: 726628
GnomAD4 genome 0.00145 AC: 221AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105AN XY: 74470
ClinVar
Submissions by phenotype
Aicardi-Goutieres syndrome 2 Pathogenic:32
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The c.529G>A;p.(Ala177Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:1262; PMID: 29691679; 29239743; 16845400; 17846997;28762473) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:25274781; 19015152, 26903602) - PS3_moderate. The variant is present at low allele frequencies population databases (rs75184679 – gnomAD 0.01452%; ABraOM 0.002989 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala177Thr) was detected in trans with a pathogenic variant (PMID: 16845400; 17846997; 28762473) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 28762473) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:16845400). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:25274781). PS4-Moderate => Recurrent mutation observed in multiple unrelated patients. (PMID:16845400,17846997,20131292,26846091,28762473). -
The observed missense c.529G>A p.Ala177Thr variant in RNASEH2B gene has been reported in homozygous state in individuals affected with Aicardi-Goutières Syndrome Beysen D et al. 2021; Videira G et al. 2020. Experimental studies have shown that this missense change affects RNASEH2B function Mackenzie et al. 2016. The p.Ala177Thr variant has allele frequency of 0.1% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as likely Pathogenic/ Pathogenic multiple submitters. Multiple lines of computational evidence Polyphen - Probabaly Damaging, SIFT - Damaging and MutationTaster - Disease causing predict damaging effect on protein structure and function for this variant. The reference amino acid in RNASEH2B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 177 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
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This variant was identified in a 5 year old female with profound intellectual disability, arching, irritability, stereotypy, sleep problems, axial hypotonia, lower extremity hypertonia, optic nerve hypoplasia, feeding problems, plagiocephaly, slender fingers, and slender big toe. A brain MRI at age 3 months showed some thinning of falx cerebri. This variant has been reported previously in the literature and ClinVar as pathogenic. A second RNASEH2B variant was not identified, adequate sequence coverage was verified and deletion/duplication analysis was also normal. Additional genetic testing, including chromosomal microarray and mitochondrial DNA sequencing and deletion analysis, have not yielded a diagnosis. -
The RNASEH2B c.529G>A (p.Ala177Thr) variant has been reported in the homozygous and compound heterozygous state in many individuals affected with AGS and related disorders (Beysen D et al., PMID: 33967934; Crow YJ et al., PMID: 16845400; Lambe J et al., PMID: 31920009; Pizzi S et al., PMID: 25274781; Rice G et al., PMID: 17846997; Videira G et al., PMID: 32258229). In at least three families, affected individuals who were homozygous for this variant showed marked intrafamilial and interfamilial phenotypic variability (Videira G et al., PMID: 32258229). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant in by several submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.2% in the European (non-Finnish) population which is compatible with carrier status for AGS and consistent with this variant being the most commonly identified causative variant (Rice G et al., PMID: 17846997). While computational predictors are uncertain as to the impact of this variant on the RNASEH2B protein, functional studies have shown a modest alteration of enzymatic activity and homozygous knock-in mice recapitulate the interferon-stimulated gene signature observed in human patients with AGS (Chon H et al., PMID: 19015152; Mackenzie KJ et al., PMID: 26903602; Perrino FW et al., PMID: 19034401; Pizzi S et al., PMID: 25274781). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Criteria applied: PM3_VSTR,PS3_MOD -
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PM3_Strong, PS3 -
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The p.Ala177Thr variant in the RNASEH2B gene has been previously reported in >20 unrelated individuals with Aicardi-Goutières syndrome (Garau et al., 2019). All individuals were homozygous or compound heterozygous. This variant has also been identified in 290/129,040 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Well-established in vivo and in vitro functional studies of the p.Ala177Thr variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Mackenzie et al., 2016; Pizzi et al., 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ala177Thr variant as pathogenic for autosomal recessive Aicardi-Goutières syndrome based on the information above. [ACMG evidence codes used: PS3; PM3_Strong -
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RNASEH2B NM_024570.3 exon 7 p.Ala177Thr (c.529G>A):This variant has been reported in the literature in numerous individuals with Aicardi-Goutieres syndrome (AGS) in the compound heterozygous and homozygous state and is reported to be the most common pathogenic variant associated with this condition (Selected publications: Crow 2006 PMID:16845400, Al-Mutairi 2018 PMID:29239743, Issa 2020 PMID:32404165, Videira 2020 PMID:32258229). This variant is present in 0.2% (40/15278) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-50945445-G-A?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:1262). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies, including a knock-in mouse model predict that this variant will impact the protein and result in downstream instability (Lim 2015 PMID:26182405, Pizzi 2015 PMID:25274781, Mackenzie 2016 PMID:26903602). However, these studies may not accurately represent in vivo biological function and at least one study suggests that the ribonuclease H activities from this variant were comparable to WT (Perrino 2009 PMID:19034401). In summary, this variant is classified as pathogenic based on the data above. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Aicardi-Goutieres syndrome 2 (MIM#610181). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Severity varies among patients (OMIM, PMID: 32258229). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 570 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RNase H2 complex component wHTH domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic in multiple individuals (ClinVar) and as homozygous in five patients from three families with differing presentations of Aicardi-Goutieres syndrome (PMID: 32258229). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PS3. -
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This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant was previously reported in individuals with Aicardi-Goutieres syndrome in homozygous as well as compound heterozygous state and segregated with the disease [PMID: 16845400, 17846997, 18754903, 26182405, 26846091, 25604658]. Functional studies have shown that this variant affects RNASEH2B function [PMID: 19015152, 19034401, 26903602]. -
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This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the RNASEH2B protein (p.Ala177Thr). This variant is present in population databases (rs75184679, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Aicardi-Goutières syndrome, and unspecified neurological disorders (PMID: 16845400, 17846997, 18754903, 19694776, 20131292, 25243380, 25343331, 25604658, 26182405, 26846091). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1262). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. Experimental studies have shown that this missense change affects RNASEH2B function (PMID: 19015152, 19034401, 26903602). For these reasons, this variant has been classified as Pathogenic. -
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The homozygous p.Ala177Thr variant in RNASEH2B was identified by our study in one individual with Aicardi-Goutieres Syndrome. The p.Ala177Thr variant is pathogenic based off of multiple reports in ClinVar and the literature. -
The RNASEH2B c.529G>A (p.Ala177Thr) missense variant results in the substitution of alanine at amino acid position 177 with threonine. Across a selection of the available literature, this variant has been reported in at least 22 individuals in a homozygous state and at least 12 individuals in a compound heterozygous state, including a sibling pair (PMID: 25604658; PMID: 29239743; PMID: 31130681; PMID: 30826161; PMID: 18754903). The highest frequency of this allele in the Genome Aggregation Database is 0.002618 in the Latino/Admixed American population (version 3.1.2). This frequency is consistent with the fact that it is the mostly commonly identified variant in individuals with Aicardi-Goutieres syndrome (PMID: 25243380; PMID: 31130681). Structural and functional studies, including in patient fibroblasts and mouse embryonic fibroblasts from an orthologous knock-in model, have demonstrated that the p.Ala177Thr substitution reduces RNase H2 subunit expression, disrupts the interaction interface of RNASEH2B with RNASEH2C, impairs complex stability, and reduces cellular RNase H2 activity (PMID: 26903602; PMID: 21177858; PMID: 21177854). Homozygous knock-in mice also recapitulate the interferon-stimulated gene signature observed in human patients with Aicardi-Goutieres syndrome. Based on the available evidence, the c.529G>A (p.Ala177Thr) variant is classified as pathogenic for Aicardi-Goutieres syndrome. -
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The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29300372). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.71 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001687316 /PMID: 32380161).Different missense changes at the same codon (p.Lys450Glu, p.Lys450Thr) have been reported to be associated with MYH7 related disorder (PMID: 10065021, 15563892). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 strong, PP1 supporting -
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not provided Pathogenic:14
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There is inter- and intra-familial variability in the presentations of individuals who are homozygous for this variant, and mildly symptomatic and asymptomatic individuals have been reported; however, neuroimaging was not performed on the asymptomatic individual (PMID: 32258229); Lymphoblastoid cells derived from a patient who harbored the A177T variant showed a destabilizing effect on the RNase H2 protein; however, it is unclear if this perturbation is solely due to the effect of the A177T variant (PMID: 25274781); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: no PMID, 33872687, 34758253, 31980526, 16845400, 19034401, 26903602, 21177854, 25604658, 27539236, 25343331, 26182405, 33967934, 33307271, 29030706, 29691679, 29239743, 30609409, 30223285, 30111349, 31367981, 31529068, 31920009, 31130284, 32404165, 34573280, 25500883, 34426522, 31589614, 33258288, 32342562, 34042169, 37296061, 36705819, 36775013, 25243380, 36430958, 36964972, 27943079, 34490615, 33177673, 35012964, 37273706, 37547187, 37267771, 32258229, 25274781) -
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RNASEH2B: PM3:Very Strong, PM2, PS3:Supporting -
PM3_very_strong, PS3, PS4_moderate -
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Aicardi Goutieres syndrome Pathogenic:2
Variant summary: RNASEH2B c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change located in the Ribonuclease H2 subunit B, wHTH domain (IPR019024) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251300 control chromosomes. c.529G>A has been widely reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Aicardi Goutieres Syndrome (example, Crow_2006, Beysen_2021). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The p.Ala177Thr variant (NM_024570.3 c.529G>A) in RNASEH2B has been reported in >50 homozygous and 7 compound heterozygous individuals with Aicardi-Goutieres sy ndrome related disorders (progressive spastic paraplegia), and segregated with d isease in at least 2 siblings (Rump 2016, Rice 2007, Crow 2006, Crow 2014, La Pi ana 2014, Crow 2015 and Ramatani 2010). Another >50 individuals were heterozygou s for this variant, though it is unclear if they were compound heterozygous for another variant in this gene or not. Although a second variant was not identifie d in a large number of individuals, the allele frequency in cases is statistical ly significantly increased compared to the general population (168/446 from lite rature vs 128/66494 ExAC, p value 0.0001 (Chi-square with Yates correction), sug gesting a causative role. This variant has also been reported in ClinVar (Variat ion ID#1262) as pathogenic by multiple laboratories. In vitro functional studies provide conflicting data ( Lim 2015 and Pizzi 2015). Homozygous mouse models de monstrate phenotypes similar to Aicardi-Goutieres syndrome (Mackenzie 2016). Thi s variant has been identified in 0.19% (128/66494) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs75 184679). Although this variant has been seen in the general population, its freq uency is low enough to be consistent with a recessive carrier frequency. In summ ary, although additional studies are required to fully establish its clinical si gnificance, the p.Ala177Thr variant is likely pathogenic for Aicardi-Goutieres s yndrome in an autosomal recessive manner based upon segregation studies, animal models, functional evidence and its occurrence in patients with this disease. -
Inborn genetic diseases Pathogenic:1
The c.529G>A (p.A177T) alteration is located in exon 7 (coding exon 7) of the RNASEH2B gene. This alteration results from a G to A substitution at nucleotide position 529, causing the alanine (A) at amino acid position 177 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.14% (386/282704) total alleles studied. The highest observed frequency was 0.22% (290/129040) of European (non-Finnish) alleles. This variant has been identified in multiple homozygous individuals with Aicardi-Goutières Syndrome (Rice, 2007; Crow, 2015; Videira, 2020; Beysen, 2021). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -
RNASEH2B-related disorder Pathogenic:1
The RNASEH2B c.529G>A variant is predicted to result in the amino acid substitution p.Ala177Thr. This is the most common causative variant in the RNASEH2B gene. The c.529G>A variant has been observed in over twenty unrelated families to be causative for Aicardi-Goutiéres syndrome and in two families with uncomplicated spastic paraplegia (Crow et al. 2006. PubMed ID: 16845400; Crow et al. 2014. PubMed ID: 25243380; Rice et al. 2007. PubMed ID: 17846997). Functional studies have shown that this variant destabilizes the RNase H2 protein complex (Pizzi et al. 2015. PubMed ID: 25274781). In summary, we classify this variant as pathogenic. -
Abnormality of the nervous system Pathogenic:1
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Autism spectrum disorder Pathogenic:1
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Cerebral palsy Pathogenic:1
missense mutation, previously described as pathogenic in the literature and in ClinVar -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at