3-142503442-A-G

Variant names:

• chr3-142503442-A-G
• rs2227931
• NM_001184.4:c.5208T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001184.4(ATR):​c.5208T>C​(p.Tyr1736Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,587,382 control chromosomes in the GnomAD database, including 120,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9419 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111354 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-142503442-A-G is Benign according to our data. Variant chr3-142503442-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 157992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142503442-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.5208T>C	p.Tyr1736Tyr	synonymous_variant	Exon 30 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.5208T>C	p.Tyr1736Tyr	synonymous_variant	Exon 30 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51985 AN: 151962 Hom.: 9415 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.360 AC: 89658 AN: 248974 Hom.: 16847 AF XY: 0.362 AC XY: 48800 AN XY: 134710

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.362

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.390

GnomAD4 exome AF: 0.389 AC: 558182 AN: 1435302 Hom.: 111354 Cov.: 28 AF XY: 0.387 AC XY: 276871 AN XY: 715200

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.381

GnomAD4 genome AF: 0.342 AC: 52007 AN: 152080 Hom.: 9419 Cov.: 32 AF XY: 0.342 AC XY: 25397 AN XY: 74328

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.371

Alfa AF: 0.397 Hom.: 18214

Bravo AF: 0.337

Asia WGS AF: 0.323 AC: 1119 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

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.5208C>T in ATR gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing. The variant is present in the control population dataset of ExAC at frequency of 36%. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.00006% in this gene, suggesting that it is a benign common polymorphism. The variant of interest has been reported as Benign/Polymorphism by a clinical laboratory and a published report (Durocher et al., 2006). Taken together, based on the prevalence in general population the variant was classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seckel syndrome 1 Benign:2

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. -

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely 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	-0.52
CADD	Benign	5.2
DANN	Benign	0.53
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: rs2227931; hg19: chr3-142222284; COSMIC: COSV63386201; COSMIC: COSV63386201;