chr3-142550233-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184.4(ATR):c.2875G>A(p.Val959Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,614,104 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 29 hom., cov: 32)

Exomes 𝑓: 0.020 ( 370 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.30

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019941628).

BP6

Variant 3-142550233-C-T is Benign according to our data. Variant chr3-142550233-C-T is described in ClinVar as [Benign]. Clinvar id is 157974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142550233-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.018 (2741/152312) while in subpopulation SAS AF= 0.0412 (199/4830). AF 95% confidence interval is 0.0365. There are 29 homozygotes in gnomad4. There are 1289 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.2875G>A	p.Val959Met	missense_variant	Exon 14 of 47	ENST00000350721.9	NP_001175.2	Q13535-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 link	c.2875G>A	p.Val959Met	missense_variant	Exon 14 of 47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2740

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0416

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0182

AC:

4585

AN:

251364

Hom.:

AF XY:

0.0197

AC XY:

2674

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.0112

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0424

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0199

AC:

29026

AN:

1461792

Hom.:

370

Cov.:

AF XY:

0.0204

AC XY:

14866

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0203

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.0307

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0412

Gnomad4 FIN exome

AF:

0.00376

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0227

GnomAD4 genome

AF:

0.0180

AC:

2741

AN:

152312

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1289

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0412

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0180

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0190

AC:

2302

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0224

EpiControl

AF:

0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Breakthrough Genomics, Breakthrough Genomics

Significance: 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.2875G>A variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a neutral outcome. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 1.9% which includes 48 homozygous occurrences, strong evidence this variant is a benign polymorphism. The variant has been reported as benign by a reputable clinical lab. Taken together, this variant has been classified as Benign. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 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

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seckel syndrome 1

Benign:3

Feb 08, 2023

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. -

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Benign:2

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.065

DEOGEN2

Benign

0.033

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.4

PrimateAI

Benign

0.38

PROVEAN

Benign

0.11

REVEL

Benign

0.065

Sift

Benign

1.0

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.019

MPC

0.16

ClinPred

0.012

GERP RS

4.3

Varity_R

0.026

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over