rs78635798

Positions:

chr11-65720385-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_032193.4(RNASEH2C):c.205C>T(p.Arg69Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RNASEH2C
NM_032193.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15U:1

Conservation

PhyloP100: 1.62

Variant links:

Genes affected

RNASEH2C (HGNC:24116): (ribonuclease H2 subunit C) This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

RNASEH2C links:

RNASEH2C (HGNC:):

RNASEH2C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a strand (size 4) in uniprot entity RNH2C_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_032193.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 11-65720385-G-A is Pathogenic according to our data. Variant chr11-65720385-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1260.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=12, Likely_pathogenic=2}. Variant chr11-65720385-G-A is described in Lovd as [Pathogenic]. Variant chr11-65720385-G-A is described in Lovd as [Pathogenic]. Variant chr11-65720385-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2C	NM_032193.4 linkuse as main transcript	c.205C>T	p.Arg69Trp	missense_variant	2/4	ENST00000308418.10	NP_115569.2	Q8TDP1A0A024R5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2C	ENST00000308418.10 linkuse as main transcript	c.205C>T	p.Arg69Trp	missense_variant	2/4	1	NM_032193.4	ENSP00000308193.5		Q8TDP1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000917

AC:

AN:

250836

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 3

Pathogenic:11Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23322642) (PMID:16845400). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple patients. (PMID:17846997,16845400,20131292,23322642,29150899). -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.205C>T (p.Arg69Trp) variant in RNASEH2C gene has been reported in homozygous state in individuals affected with Aicardi-Goutieres syndrome 3 (Nishimura T et al. 2019; Hebbar M et al. 2018). Functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Reijns et al., 2011). The p.Arg69Trp variant has allele frequency of 0.01% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The reference amino acid p.Arg69Trp in RNASEH2C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen-damaging, SIFT-damaging and Mutation Taster- disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Arginine at position 69 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 04, 2022	A homozygous missense variation in exon 2 of the RNASEH2C gene that results in the amino acid substitution of Valine for Arginine at codon 69 was detected. The observed variant c.205C>T (p.Arg69Trp) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.205C>T in Exon 2 of the RNASEH2C gene that results in the amino acid substitution p.Arg69Trp was identified. The observed variant has allele frequency of 0.00009/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic(ClinVar ID: 1260). Functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Chon H et al., 2009). c.205C>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Aicardi Goutieres Syndrome and is reported as a frequent founder mutation of Asian origin (Kaur P et al., 2021 and Rice G et al., 2007). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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 3 (MIM#610329). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (23 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ribonuclease H2 non-catalytic subunit (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity. It has been reported in more than 30 patients in a homozygous state and is likely a founder mutation in the South Asian population (ClinVar, PMIDs: 17846997, 20131292, 29150899). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant causes a decrease in RNase enzyme activity and stability (PMIDs: 19015152, 31529068). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PS3,PM3 (strong), PP3,PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Nov 11, 2024	A known variant, c.205C>T in exon 2 of RNASEH2C was observed in a homozygous state in proband (ClinVar ID: 1260) (Hebbar et al., 2018). Sanger validation and segregation analysis revealed that, the variant was present in homozygous state in proband and heterozygous state in his mother (Lab ID: 9426). The variant was absent in his father (Lab ID: 9427). This variant is observed in 61 individuals in the gnomAD population database (v4.1.0) (Allele frequency: 0.00003968) and in four individuals in our in-house database of 3267 individuals in a heterozygous state. The variant c.205C>T in a homozygous state was seen in five individuals in our in-house data with AicardiGoutieres syndrome 3 (Hebbar et al., 2018). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001260, PMID:16845400, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 19015152, 21177854, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.709, PP3_P). A missense variant is a common mechanism associated with Aicardi-Goutieres syndrome 3 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000092, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 69 of the RNASEH2C protein (p.Arg69Trp). This variant is present in population databases (rs78635798, gnomAD 0.07%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845400, 23322642, 29150899, 29239743). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1260). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2C function (PMID: 19015152, 19034401, 31529068). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	Published functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Chon et al., 2009; Reijns et al., 2011); This variant is associated with the following publications: (PMID: 25604658, 31529068, 29239743, 17846997, 21177854, 19034401, 19015152, 26456534, 23322642, 20131292, 16845400, 29150899, 27391121, 24123366, 29302074, 32180488) -

Aicardi Goutieres syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2022

Variant summary: RNASEH2C c.205C>T (p.Arg69Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250836 control chromosomes, predominantly at a frequency of 0.00072 within the South Asian subpopulation in the gnomAD database. c.205C>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Aicardi Goutieres Syndrome and is reported as a frequent founder mutation of Asian origin (example, Rice_2007, Vogt_2013, Kaur_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Nishimura_2019). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Benign

0.14

Eigen_PC

Benign

-0.033

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.89

.;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.031

D;D

Polyphen

1.0

D;.

Vest4

0.66

MutPred

0.88

Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);

MVP

0.99

MPC

1.2

ClinPred

0.70

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over