19-12807328-C-T

Variant names:

• chr19-12807328-C-T
• rs76436818
• NM_006397.3:c.322C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006397.3(RNASEH2A):​c.322C>T​(p.Arg108Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNASEH2A NM_006397.3 missense, splice_region
• Scores: Splicing: ADA: 0.4922
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 1.73
• Publications: 13 publications found

Genes affected

RNASEH2A (HGNC:18518): (ribonuclease H2 subunit A) The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres Syndrome (AGS), a an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[provided by RefSeq, Aug 2009]

THSD8 (HGNC:53785): (thrombospondin type 1 domain containing 8)

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 19-12807328-C-T is Pathogenic according to our data. Variant chr19-12807328-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126397.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2A	NM_006397.3	c.322C>T	p.Arg108Trp	missense_variant, splice_region_variant	Exon 3 of 8	ENST00000221486.6	NP_006388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.322C>T	p.Arg108Trp	missense_variant, splice_region_variant	Exon 3 of 8	1	NM_006397.3	ENSP00000221486.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251478 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Pathogenic:2 Uncertain:1 Other:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.R108W in RNASEH2A (NM_006397.3) has ben previously reported in affected patients (Stephanie R Coffin et al). Functional studies have not been performed. It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD ExomesThe p.R108W variant is novel (not in any individuals) in 1000 Genomes. In silico tools predict the variant to be damaging and the residue is moderately conserved across species. For these reasons, this variant has been classified as Likely Pathogenic. -

Sep 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 126397). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2A function (PMID: 21454563). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 31130681). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 108 of the RNASEH2A protein (p.Arg108Trp). -

Aicardi Goutieres syndrome Pathogenic:1

Apr 09, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RNASEH2A c.322C>T (p.Arg108Trp) results in a non-conservative amino acid change located in the Ribonuclease HII/HIII domain (IPR024567) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, the variant affects the penultimate nucleotide of exon 3, therefore might also affect splicing. Several computational tools predict a significant impact on normal splicing: one predict the variant no significant impact on splicing, two predict the variant weakens a 5' donor site, while one predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251478 chromosomes (gnomAD v2.1). The variant c.322C>T has been reported in the literature in compound heterozygous- and homozygous individuals affected with Aicardi Goutieres Syndrome (e.g. Rice_2007, Rice_2013, Garau_2019, Ganapathy_2019, Wang_2022). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated moderately decreased catalytic efficiency and nucleic acid binding (Coffin_2011), however, since authors used bacterially expressed (intronless) cDNA constructs (which don't undergo splicing) therefore the activities in these assays might not reflect the overall in vivo consequences of this variant. In addition, mitochondrial dysfunction was reported in lymphoblastoid cell lines (LCLs), derived from a compound heterozygous patient (Dragoni_2022). The following publications have been ascertained in the context of this evaluation (PMID: 17846997, 24183309, 33707687, 31069529, 35551623, 21454563, 36430958). ClinVar contains an entry for this variant (Variation ID: 126397). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Mar 02, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect on catalytic efficiency and binding affinity (PMID: 21454563); In silico analyses support that this missense variant has a deleterious effect on protein structure/function and a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 36430958, 31069529, 31130681, 17846997, 35551623, 33707687, 21454563) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.4	M;.
PhyloP100		1.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.5	D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.85		Loss of methylation at R108 (P = 0.031);.;
MVP		0.99
MPC		0.83
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.96
gMVP		0.81
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.49
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: -2

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

Other links and lift over

dbSNP: rs76436818; hg19: chr19-12918142; COSMIC: COSV55551469; COSMIC: COSV55551469;