3-142562456-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.946G>A(p.Val316Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,614,050 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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: 33)

Exomes 𝑓: 0.020 ( 370 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.07

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=0.006286353).

BP6

Variant 3-142562456-C-T is Benign according to our data. Variant chr3-142562456-C-T is described in ClinVar as [Benign]. Clinvar id is 158006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142562456-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0178 (2712/152268) while in subpopulation SAS AF= 0.0411 (198/4818). AF 95% confidence interval is 0.0364. There are 29 homozygotes in gnomad4. There are 1275 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.946G>A	p.Val316Ile	missense_variant	Exon 4 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.946G>A	p.Val316Ile	missense_variant	Exon 4 of 47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2712

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0181

AC:

4559

AN:

251222

Hom.:

AF XY:

0.0196

AC XY:

2662

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0423

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.0183

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0198

AC:

28998

AN:

1461782

Hom.:

370

Cov.:

AF XY:

0.0204

AC XY:

14848

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0200

Gnomad4 AMR exome

AF:

0.0113

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:

0.0178

AC:

2712

AN:

152268

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1275

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0211

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0411

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.0184

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0190

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.0211

AC:

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0189

AC:

2290

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0224

EpiControl

AF:

0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: 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

Feb 08, 2023

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. -

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

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

Eigen

Benign

-0.14

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.40

PROVEAN

Benign

0.080

REVEL

Benign

0.034

Sift

Benign

0.24

Sift4G

Benign

0.33

Polyphen

0.022

Vest4

0.043

MPC

0.14

ClinPred

0.0072

GERP RS

4.4

Varity_R

0.050

gMVP

0.15

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