3-142459302-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001184.4(ATR):c.7274G>A(p.Arg2425Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,772 control chromosomes in the GnomAD database, including 18,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2425L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1344 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16859 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0370

Publications

70 publications found

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 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

ATR links:

ENSG00000295506 (HGNC:):

ENSG00000295506 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001532197).

BP6

Variant 3-142459302-C-T is Benign according to our data. Variant chr3-142459302-C-T is described in ClinVar as Benign. ClinVar VariationId is 136470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.7274G>A	p.Arg2425Gln	missense_variant	Exon 43 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 link	c.7274G>A	p.Arg2425Gln	missense_variant	Exon 43 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19374

AN:

152002

Hom.:

1340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0810

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0845

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.0982

Gnomad FIN

AF:

0.163

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.135

GnomAD2 exomes

AF:

0.131

AC:

32811

AN:

251230

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.0795

Gnomad AMR exome

AF:

0.0994

Gnomad ASJ exome

AF:

0.0798

Gnomad EAS exome

AF:

0.0982

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.149

AC:

217372

AN:

1461652

Hom.:

16859

Cov.:

AF XY:

0.147

AC XY:

106950

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0736

AC:

2465

AN:

33474

American (AMR)

AF:

0.101

AC:

4513

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0794

AC:

2074

AN:

26126

East Asian (EAS)

AF:

0.114

AC:

4541

AN:

39678

South Asian (SAS)

AF:

0.100

AC:

8636

AN:

86246

European-Finnish (FIN)

AF:

0.167

AC:

8918

AN:

53412

Middle Eastern (MID)

AF:

0.105

AC:

608

AN:

5768

European-Non Finnish (NFE)

AF:

0.159

AC:

177307

AN:

1111846

Other (OTH)

AF:

0.138

AC:

8310

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

11116

22232

33348

44464

55580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6100

12200

18300

24400

30500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.127

AC:

19375

AN:

152120

Hom.:

1344

Cov.:

AF XY:

0.125

AC XY:

9319

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0808

AC:

3356

AN:

41532

American (AMR)

AF:

0.110

AC:

1675

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0845

AC:

293

AN:

3468

East Asian (EAS)

AF:

0.101

AC:

522

AN:

5160

South Asian (SAS)

AF:

0.0989

AC:

477

AN:

4824

European-Finnish (FIN)

AF:

0.163

AC:

1727

AN:

10580

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.160

AC:

10888

AN:

67962

Other (OTH)

AF:

0.137

AC:

289

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

859

1718

2576

3435

4294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.144

Hom.:

6024

Bravo

AF:

0.120

TwinsUK

AF:

0.161

AC:

597

ALSPAC

AF:

0.147

AC:

568

ESP6500AA

AF:

0.0881

AC:

388

ESP6500EA

AF:

0.158

AC:

1357

ExAC

AF:

0.133

AC:

16083

Asia WGS

AF:

0.0990

AC:

347

AN:

3478

EpiCase

AF:

0.155

EpiControl

AF:

0.150

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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 -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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.7274G>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 13.3% which includes 1212 homozygous occurrences, strong evidence this variant is a benign polymorphism. The variant has been reported as benign by multiple reputable clinical labs/publications. Taken together, this variant has been classified as Benign. -

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.68

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.053

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.61

PhyloP100

0.037

PrimateAI

Benign

0.24

PROVEAN

Benign

0.040

REVEL

Benign

0.17

Sift

Benign

0.56

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.022

MPC

0.72

ClinPred

0.0046

GERP RS

-9.1

Varity_R

0.046

gMVP

0.072

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over