rs7247284

Variant names:

• chr19-12810372-T-C
• rs7247284
• NM_006397.3:c.605T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.940
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• 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 VariationId is 259974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
RNASEH2A	NM_006397.3	c.605T>C	p.Leu202Ser	missense_variant	Exon 6 of 8	ENST00000221486.6	NP_006388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.605T>C	p.Leu202Ser	missense_variant	Exon 6 of 8	1	NM_006397.3	ENSP00000221486.4

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10056 AN: 152050 Hom.: 534 Cov.: 32

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

GnomAD2 exomes AF: 0.0474 AC: 11915 AN: 251458 AF XY: 0.0426

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 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.: 33 AF XY: 0.0360 AC XY: 26188 AN XY: 727214

African (AFR) AF: 0.150 AC: 5028 AN: 33478

American (AMR) AF: 0.105 AC: 4712 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0420 AC: 1098 AN: 26134

East Asian (EAS) AF: 0.0110 AC: 438 AN: 39700

South Asian (SAS) AF: 0.0283 AC: 2445 AN: 86258

European-Finnish (FIN) AF: 0.0273 AC: 1460 AN: 53420

Middle Eastern (MID) AF: 0.0494 AC: 285 AN: 5766

European-Non Finnish (NFE) AF: 0.0321 AC: 35747 AN: 1111954

Other (OTH) AF: 0.0420 AC: 2538 AN: 60396

GnomAD4 genome AF: 0.0663 AC: 10093 AN: 152168 Hom.: 540 Cov.: 32 AF XY: 0.0656 AC XY: 4878 AN XY: 74398

African (AFR) AF: 0.145 AC: 6036 AN: 41518

American (AMR) AF: 0.0699 AC: 1068 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3470

East Asian (EAS) AF: 0.0172 AC: 89 AN: 5160

South Asian (SAS) AF: 0.0276 AC: 133 AN: 4824

European-Finnish (FIN) AF: 0.0283 AC: 300 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2142 AN: 68002

Other (OTH) AF: 0.0545 AC: 115 AN: 2110

Alfa AF: 0.0409 Hom.: 928

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aicardi-Goutieres syndrome 4 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.9
DANN	Benign	0.25
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.94
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.15
Sift	Benign	0.74	T
Sift4G	Benign	0.75	T
Polyphen		0.0060	B
Vest4		0.089
MPC		0.30
ClinPred		0.0012	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.61
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7247284; hg19: chr19-12921186; COSMIC: COSV55551431; COSMIC: COSV55551431;