3-142449489-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001184.4(ATR):c.7875G>A(p.Gln2625=) 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:11
• Conservation: PhyloP100: 1.24

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 -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. Variant chr3-142449489-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ATR	NM_001184.4	c.7875G>A	p.Gln2625=	synonymous_variant	47/47	ENST00000350721.9
ATR	NM_001354579.2	c.7683G>A	p.Gln2561=	synonymous_variant	46/46
ATR	XM_011512924.2	c.7881G>A	p.Gln2627=	synonymous_variant	47/47
ATR	XM_011512925.2	c.7689G>A	p.Gln2563=	synonymous_variant	46/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.7875G>A	p.Gln2625=	synonymous_variant	47/47	1	NM_001184.4	P1

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

GnomAD3 exomes AF: 0.858 AC: 215739 AN: 251404 Hom.: 93115 AF XY: 0.863 AC XY: 117273 AN XY: 135880

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 SAS exome AF: 0.937

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

Gnomad4 AFR exome AF: 0.974

Gnomad4 AMR exome AF: 0.765

Gnomad4 ASJ exome AF: 0.775

Gnomad4 EAS exome AF: 0.908

Gnomad4 SAS exome AF: 0.935

Gnomad4 FIN exome AF: 0.810

Gnomad4 NFE exome AF: 0.868

Gnomad4 OTH exome AF: 0.876

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

Gnomad4 AFR AF: 0.970

Gnomad4 AMR AF: 0.806

Gnomad4 ASJ AF: 0.784

Gnomad4 EAS AF: 0.929

Gnomad4 SAS AF: 0.939

Gnomad4 FIN AF: 0.804

Gnomad4 NFE AF: 0.866

Gnomad4 OTH AF: 0.874

Alfa AF: 0.865 Hom.: 92734

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 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 -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Seckel syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	3.3
Dann	Benign	0.79

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: rs1802904; hg19: chr3-142168331; COSMIC: COSV99377126; COSMIC: COSV99377126;