rs753679297

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_006397.3(RNASEH2A):c.557G>A(p.Arg186Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,888 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RNASEH2A
NM_006397.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 8.78

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 18 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-12810323-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 19-12810324-G-A is Pathogenic according to our data. Variant chr19-12810324-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 445579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12810324-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2A	NM_006397.3 link	c.557G>A	p.Arg186Gln	missense_variant	Exon 6 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.557G>A	p.Arg186Gln	missense_variant	Exon 6 of 8	1	NM_006397.3	ENSP00000221486.4		O75792

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 4

Pathogenic:7

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3(strong),PM2,PP3,PP1,PM5 -

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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 186 of the RNASEH2A protein (p.Arg186Gln). This variant is present in population databases (rs753679297, gnomAD 0.0009%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 24300241, 29239743). ClinVar contains an entry for this variant (Variation ID: 445579). 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%. For these reasons, this variant has been classified as Pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 12, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 04, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM5, PP3, PP5 -

not provided

Pathogenic:4

Oct 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second RNASEH2A variant, phase unknown, in an individual with Aicardi-Goutieres syndrome (Abe et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29239743, 34374989, 31130284, 24300241, 36065636) -

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 02, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557G>A (p.R186Q) alteration is located in exon 6 (coding exon 6) of the RNASEH2A gene. This alteration results from a G to A substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/251488) total alleles studied. This variant has been reported in the homozygous and compound heterozygous state in patients with features of Aicardi-Goutières syndrome (Abe, 2014; Al Mutairi, 2018; Monies, 2017; Monies, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

RNASEH2A-related disorder

Pathogenic:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RNASEH2A c.557G>A variant is predicted to result in the amino acid substitution p.Arg186Gln. This variant has been reported many times in both the homozygous and compound heterozygous states in individuals with Aicardi-Goutieres syndrome (see for examples, Abe et al. 2014. PubMed ID: 24300241; Al Mutairi et al. 2017. PubMed ID: 29239743; Table S1, Monies et al. 2019. PubMed ID: 31130284; Saleh et al. 2021. PubMed ID: 34374989). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/445579/). Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.9

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.94

Gain of catalytic residue at R186 (P = 0.0107);

MVP

0.98

MPC

0.88

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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