rs7247284

Positions:

chr19-12810372-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_006397.3(RNASEH2A):c.605T>C(p.Leu202Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,613,998 control chromosomes in the GnomAD database, including 1,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. L202L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.066 ( 540 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1409 hom. )

Consequence

RNASEH2A
NM_006397.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.940

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 Benign. Variant got -18 ACMG points.

PM1

In a domain RNase H type-2 (size 222) in uniprot entity RNH2A_HUMAN there are 22 pathogenic changes around while only 8 benign (73%) in NM_006397.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0019553006).

BP6

Variant 19-12810372-T-C is Benign according to our data. Variant chr19-12810372-T-C is described in ClinVar as [Benign]. Clinvar id is 259974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12810372-T-C is described in Lovd as [Benign]. Variant chr19-12810372-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3 linkuse as main transcript	c.605T>C	p.Leu202Ser	missense_variant	6/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6 linkuse as main transcript	c.605T>C	p.Leu202Ser	missense_variant	6/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10056

AN:

152050

Hom.:

534

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0701

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.0172

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0283

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0315

Gnomad OTH

AF:

0.0546

GnomAD3 exomes

AF:

0.0474

AC:

11915

AN:

251458

Hom.:

471

AF XY:

0.0426

AC XY:

5795

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.0433

Gnomad EAS exome

AF:

0.0176

Gnomad SAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.0275

Gnomad NFE exome

AF:

0.0301

Gnomad OTH exome

AF:

0.0398

GnomAD4 exome

AF:

0.0368

AC:

53751

AN:

1461830

Hom.:

1409

Cov.:

AF XY:

0.0360

AC XY:

26188

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.150

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.0420

Gnomad4 EAS exome

AF:

0.0110

Gnomad4 SAS exome

AF:

0.0283

Gnomad4 FIN exome

AF:

0.0273

Gnomad4 NFE exome

AF:

0.0321

Gnomad4 OTH exome

AF:

0.0420

GnomAD4 genome

AF:

0.0663

AC:

10093

AN:

152168

Hom.:

540

Cov.:

AF XY:

0.0656

AC XY:

4878

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.145

Gnomad4 AMR

AF:

0.0699

Gnomad4 ASJ

AF:

0.0427

Gnomad4 EAS

AF:

0.0172

Gnomad4 SAS

AF:

0.0276

Gnomad4 FIN

AF:

0.0283

Gnomad4 NFE

AF:

0.0315

Gnomad4 OTH

AF:

0.0545

Alfa

AF:

0.0381

Hom.:

444

Bravo

AF:

0.0742

TwinsUK

AF:

0.0348

AC:

129

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.140

AC:

616

ESP6500EA

AF:

0.0326

AC:

280

ExAC

AF:

0.0465

AC:

5651

Asia WGS

AF:

0.0320

AC:

111

AN:

3478

EpiCase

AF:

0.0314

EpiControl

AF:

0.0343

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Aicardi-Goutieres syndrome 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.39

CADD

Benign

3.9

DANN

Benign

0.25

DEOGEN2

Benign

0.31

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.42

REVEL

Benign

0.15

Sift

Benign

0.74

Sift4G

Benign

0.75

Polyphen

0.0060

Vest4

0.089

MPC

0.30

ClinPred

0.0012

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.61

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