NM_006397.3:c.33A>G

Variant names:

• chr19-12806706-A-G
• rs11554400
• NM_006397.3:c.33A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006397.3(RNASEH2A):​c.33A>G​(p.Thr11Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,570,774 control chromosomes in the GnomAD database, including 1,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (543 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1341 hom.)
• Consequence: RNASEH2A NM_006397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.66
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-12806706-A-G is Benign according to our data. Variant chr19-12806706-A-G is described in ClinVar as Benign. ClinVar VariationId is 259971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2A	NM_006397.3	c.33A>G	p.Thr11Thr	synonymous_variant	Exon 1 of 8	ENST00000221486.6	NP_006388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.33A>G	p.Thr11Thr	synonymous_variant	Exon 1 of 8	1	NM_006397.3	ENSP00000221486.4

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10088 AN: 152178 Hom.: 538 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0554

GnomAD2 exomes AF: 0.0467 AC: 8373 AN: 179230 AF XY: 0.0423

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0398

GnomAD4 exome AF: 0.0364 AC: 51690 AN: 1418478 Hom.: 1341 Cov.: 31 AF XY: 0.0358 AC XY: 25117 AN XY: 701666

African (AFR) AF: 0.150 AC: 4902 AN: 32588

American (AMR) AF: 0.101 AC: 3773 AN: 37536

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 1061 AN: 25322

East Asian (EAS) AF: 0.0105 AC: 394 AN: 37494

South Asian (SAS) AF: 0.0284 AC: 2300 AN: 80876

European-Finnish (FIN) AF: 0.0275 AC: 1383 AN: 50226

Middle Eastern (MID) AF: 0.0497 AC: 284 AN: 5710

European-Non Finnish (NFE) AF: 0.0322 AC: 35105 AN: 1090006

Other (OTH) AF: 0.0424 AC: 2488 AN: 58720

GnomAD4 genome AF: 0.0665 AC: 10124 AN: 152296 Hom.: 543 Cov.: 32 AF XY: 0.0657 AC XY: 4895 AN XY: 74476

African (AFR) AF: 0.146 AC: 6059 AN: 41546

American (AMR) AF: 0.0701 AC: 1073 AN: 15304

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

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5180

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4834

European-Finnish (FIN) AF: 0.0283 AC: 301 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0315 AC: 2143 AN: 68020

Other (OTH) AF: 0.0553 AC: 117 AN: 2116

Alfa AF: 0.0467 Hom.: 133

Bravo AF: 0.0745

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Benign:4

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. -

Sep 21, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

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 -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		-1.7
PromoterAI		-0.083	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11554400; hg19: chr19-12917520;