rs397515480

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_006397.3(RNASEH2A):c.69G>A(p.Val23Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,571,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

RNASEH2A
NM_006397.3 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 0.808

Variant links:

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]

RNASEH2A links:

RNASEH2A (HGNC:):

RNASEH2A links:

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

THSD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-12806742-G-A is Pathogenic according to our data. Variant chr19-12806742-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12806742-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2A	NM_006397.3 linkuse as main transcript	c.69G>A	p.Val23Val	synonymous_variant	1/8	ENST00000221486.6	NP_006388.2	O75792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2A	ENST00000221486.6 linkuse as main transcript	c.69G>A	p.Val23Val	synonymous_variant	1/8	1	NM_006397.3	ENSP00000221486.4		O75792

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

180420

Hom.:

AF XY:

0.0000104

AC XY:

AN XY:

96246

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000398

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000317

AC:

AN:

1418944

Hom.:

Cov.:

AF XY:

0.0000242

AC XY:

AN XY:

701672

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000394

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000326

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 4

Pathogenic:4Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 05, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 13, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 4 (MIM#610333). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Analysis of patient cells by RT-PCR shows this variant results in the formation of a donor splice site within exon 1, leading to an out-of-frame shift in the reading frame and the formation of a protein predicted to undergo nonsense-mediated decay (NMD) (p.(Val23Alafs*21)) (PMID: 23592335). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These variants have been reported in several patients with Aicardi-Goutieres syndrome (ClinVar, PMID: 25604658). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been described as pathogenic, and reported in at least three unrelated families with Aicardi-Goutieres syndrome (ClinVar, PMID: 25604658, PMID: 23592335, PMID: 31130681). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected lymphoblastoid cell lines have shown this variant resulted in significantly reduced enzyme activity (PMID: 23592335). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change affects codon 23 of the RNASEH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RNASEH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397515480, gnomAD 0.004%). This variant has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 23592335). ClinVar contains an entry for this variant (Variation ID: 66067). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 23592335). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aicardi Goutieres syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 09, 2021

Variant summary: RNASEH2A c.69G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: four predict the variant creates a 5' donor site. At least one publication reported experimental evidence and demonstrated that in patient derived cells this variant variant resulted in altered mRNA splicing, causing an out of frame deletion, with the insertion of 20 amino acids followed by a premature stop codon at amino acid 42 (Rice_2013). The variant allele was found at a frequency of 1.7e-05 in 180420 control chromosomes (gnomAD). c.69G>A has been reported in the literature in at least three compound heterozygous individuals affected with Aicardi Goutieres Syndrome (Rice_2013, Crow_2015 and LOVD). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and reported reduction of all three RNase H2 subunits and strongly reduced enzyme activity from patient derived cells (Rice_2013). One submitter have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2022

RT-PCR analysis demonstrated that the c.69 G>A variant forms a new splice donor site resulting in an out-of-frame deletion at the end of exon 1 leading to a premature termination codon at amino acid 42; This variant is associated with the following publications: (PMID: 17846997, 21454563, 23592335, 25604658, 31130681) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.67

Position offset: -3

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