chr3-142558733-A-T

Variant names:

• chr3-142558733-A-T
• rs2227930
• NM_001184.4:c.1776T>A

Variant summary

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

The NM_001184.4(ATR):​c.1776T>A​(p.Gly592Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,609,390 control chromosomes in the GnomAD database, including 272,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30789 hom., cov: 31)
  • Exomes 𝑓: 0.57 (241341 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.264

Genes affected

ATR (HGNC:882): (ATR serine/threonine kinase) The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-142558733-A-T is Benign according to our data. Variant chr3-142558733-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 157965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142558733-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.264 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.1776T>A	p.Gly592Gly	synonymous_variant	Exon 8 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.1776T>A	p.Gly592Gly	synonymous_variant	Exon 8 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95066 AN: 151788 Hom.: 30738 Cov.: 31

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.621

GnomAD3 exomes AF: 0.546 AC: 136880 AN: 250500 Hom.: 38556 AF XY: 0.542 AC XY: 73359 AN XY: 135456

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.564

Gnomad EAS exome AF: 0.469

Gnomad SAS exome AF: 0.432

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.572 AC: 833137 AN: 1457486 Hom.: 241341 Cov.: 36 AF XY: 0.567 AC XY: 411520 AN XY: 725186

Gnomad4 AFR exome AF: 0.805

Gnomad4 AMR exome AF: 0.463

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.548

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome AF: 0.626 AC: 95163 AN: 151904 Hom.: 30789 Cov.: 31 AF XY: 0.618 AC XY: 45910 AN XY: 74236

Gnomad4 AFR AF: 0.794

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.587

Gnomad4 OTH AF: 0.625

Alfa AF: 0.597 Hom.: 8897

Bravo AF: 0.634

Asia WGS AF: 0.505 AC: 1755 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 28, 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 -

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 20, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 27, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1776T>A variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 4/4 in silico tools via Alamut predict the variant to eliminate a cryptic splice donor site, thereby potential resulting in a protective effect on normal splicing. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 55% which includes 19,239 homozygous occurrences. Therefore this synonymous variant is the major allele and has been classified as Benign. -

Mar 03, 2015

GeneDx

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

- -

Seckel syndrome 1 Benign:2

Jul 14, 2021

Genome-Nilou Lab

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. -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.6
DANN	Benign	0.67

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: rs2227930; hg19: chr3-142277575; COSMIC: COSV63383320; COSMIC: COSV63383320;