3-142449489-C-T

Variant names:

• chr3-142449489-C-T
• rs1802904
• NM_001184.4:c.7875G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001184.4(ATR):​c.7875G>A​(p.Gln2625Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,613,102 control chromosomes in the GnomAD database, including 612,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60127 hom., cov: 32)
  • Exomes 𝑓: 0.87 (552567 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.24
• Publications: 44 publications found

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]

ATR Gene-Disease associations (from GenCC):

• Seckel syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial prostate carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000295506 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-142449489-C-T is Benign according to our data. Variant chr3-142449489-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.7875G>A	p.Gln2625Gln	synonymous_variant	Exon 47 of 47	ENST00000350721.9	NP_001175.2
ATR	NM_001354579.2	c.7683G>A	p.Gln2561Gln	synonymous_variant	Exon 46 of 46		NP_001341508.1
ATR	XM_011512924.2	c.7881G>A	p.Gln2627Gln	synonymous_variant	Exon 47 of 47		XP_011511226.1
ATR	XM_011512925.2	c.7689G>A	p.Gln2563Gln	synonymous_variant	Exon 46 of 46		XP_011511227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.7875G>A	p.Gln2625Gln	synonymous_variant	Exon 47 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134880 AN: 152128 Hom.: 60074 Cov.: 32

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.872

GnomAD2 exomes AF: 0.858 AC: 215739 AN: 251404 AF XY: 0.863

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.756

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.856

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.869 AC: 1269266 AN: 1460856 Hom.: 552567 Cov.: 52 AF XY: 0.871 AC XY: 632790 AN XY: 726804

African (AFR) AF: 0.974 AC: 32586 AN: 33462

American (AMR) AF: 0.765 AC: 34217 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20239 AN: 26118

East Asian (EAS) AF: 0.908 AC: 36011 AN: 39676

South Asian (SAS) AF: 0.935 AC: 80661 AN: 86234

European-Finnish (FIN) AF: 0.810 AC: 43281 AN: 53420

Middle Eastern (MID) AF: 0.861 AC: 4964 AN: 5766

European-Non Finnish (NFE) AF: 0.868 AC: 964425 AN: 1111102

Other (OTH) AF: 0.876 AC: 52882 AN: 60360

GnomAD4 genome AF: 0.887 AC: 134988 AN: 152246 Hom.: 60127 Cov.: 32 AF XY: 0.883 AC XY: 65740 AN XY: 74428

African (AFR) AF: 0.970 AC: 40307 AN: 41570

American (AMR) AF: 0.806 AC: 12320 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2721 AN: 3472

East Asian (EAS) AF: 0.929 AC: 4810 AN: 5178

South Asian (SAS) AF: 0.939 AC: 4540 AN: 4834

European-Finnish (FIN) AF: 0.804 AC: 8511 AN: 10582

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58922 AN: 68002

Other (OTH) AF: 0.874 AC: 1847 AN: 2114

Alfa AF: 0.866 Hom.: 112869

Bravo AF: 0.887

Asia WGS AF: 0.937 AC: 3256 AN: 3478

EpiCase AF: 0.863

EpiControl AF: 0.858

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

May 09, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

-

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 -

not provided Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 26, 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.7875G>A variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts polymorphism outcome for this variant. 3/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts changes of binding motifs for splicing enhancers. However, these predictions are not confirmed by experimental studies. This variant is found in 104951/121386 control chromosomes (45665 homozygotes) at a frequency of 0.8646055, which is about 1383368 times of the maximal expected frequency of a pathogenic allele (0.0000006) in this gene. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Seckel syndrome 1 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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	-0.40
CADD	Benign	3.3
DANN	Benign	0.79
PhyloP100		1.2
Mutation Taster		=60/40	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: rs1802904; hg19: chr3-142168331; COSMIC: COSV99377126; COSMIC: COSV99377126;