rs75718910

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_006397.3(RNASEH2A):c.704G>A(p.Arg235Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,790 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RNASEH2A
NM_006397.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 9.27

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:

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

THSD8 links:

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]

HOOK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain RNase H type-2 (size 222) in uniprot entity RNH2A_HUMAN there are 12 pathogenic changes around while only 4 benign (75%) in NM_006397.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 19-12813149-G-A is Pathogenic according to our data. Variant chr19-12813149-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12813149-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2A	NM_006397.3 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 7 of 8	ENST00000221486.6	NP_006388.2	O75792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2A	ENST00000221486.6 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 7 of 8	1	NM_006397.3	ENSP00000221486.4		O75792

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251100

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000444

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 4

Pathogenic:3Other:1

May 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 235 of the RNASEH2A protein (p.Arg235Gln). This variant is present in population databases (rs75718910, gnomAD 0.003%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 17846997, 23592335, 27943079). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as R236Q. ClinVar contains an entry for this variant (Variation ID: 66066). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RNASEH2A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RNASEH2A function (PMID: 21454563). This variant disrupts the p.Arg235 amino acid residue in RNASEH2A. Other variant(s) that disrupt this residue have been observed in individuals with RNASEH2A-related conditions (PMID: 24300241), which suggests that this may be a clinically significant amino acid residue. 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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 13, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aicardi Goutieres syndrome

Pathogenic:1

Feb 03, 2023

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.704G>A (p.Arg235Gln) results in a conservative amino acid change located in the Ribonuclease HII/HIII domain (IPR024567) 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 1.6e-05 in 251100 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.704G>A has been reported in the literature in individuals affected with Aicardi Goutieres Syndrome (e.g., Rice_2007, Rice_2013, Crow_2015). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g., Coffin_2011, Lim_2015), reporting dramatically reduced enzyme, catalytic, and substrate-binding activity (<1%, Coffin_2011) as well as genome-wide DNA:RNA hybrid accumulation and hypomethylation (Lim_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. In addition, p.R235W has been reported to associate with Aicardi-Goutieres syndrome (HGMD database).Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.98

Loss of MoRF binding (P = 0.027);

MVP

0.99

MPC

0.88

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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