rs76634951

chr19-12813343-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006397.3(RNASEH2A):c.777C>T(p.Ser259=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,052 control chromosomes in the GnomAD database, including 505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (38 hom., cov: 32)
  • Exomes 𝑓: 0.022 (467 hom.)
• Consequence: RNASEH2A NM_006397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.69

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-12813343-C-T is Benign according to our data. Variant chr19-12813343-C-T is described in ClinVar as [Benign]. Clinvar id is 328297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12813343-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.777C>T	p.Ser259=	synonymous_variant	8/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.777C>T	p.Ser259=	synonymous_variant	8/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3275 AN: 152090 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0293 AC: 7353 AN: 251156 Hom.: 178 AF XY: 0.0268 AC XY: 3646 AN XY: 135802

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.0918

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0175

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0219 AC: 32002 AN: 1461844 Hom.: 467 Cov.: 33 AF XY: 0.0216 AC XY: 15741 AN XY: 727222

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.0877

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.0239

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0215 AC: 3279 AN: 152208 Hom.: 38 Cov.: 32 AF XY: 0.0224 AC XY: 1668 AN XY: 74404

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.0219

Gnomad4 FIN AF: 0.0279

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0189 Hom.: 8

Bravo AF: 0.0236

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0189

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 specified Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.12
Dann	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs76634951; hg19: chr19-12924157; COSMIC: COSV55551440; COSMIC: COSV55551440;