chr3-142562770-A-G

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.632T>C(p.Met211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,609,006 control chromosomes in the GnomAD database, including 272,275 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M211I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.63 ( 30706 hom., cov: 32)

Exomes 𝑓: 0.57 ( 241569 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.48

Publications

92 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:

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=8.809924E-7).

BP6

Variant 3-142562770-A-G is Benign according to our data. Variant chr3-142562770-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.632T>C	p.Met211Thr	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.632T>C	p.Met211Thr	missense_variant	Exon 4 of 47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

95022

AN:

151920

Hom.:

30655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.790

Gnomad AMI

AF:

0.679

Gnomad AMR

AF:

0.534

Gnomad ASJ

AF:

0.560

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.443

Gnomad FIN

AF:

0.539

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.587

Gnomad OTH

AF:

0.621

GnomAD2 exomes

AF:

0.548

AC:

135126

AN:

246404

AF XY:

0.544

show subpopulations

Gnomad AFR exome

AF:

0.797

Gnomad AMR exome

AF:

0.456

Gnomad ASJ exome

AF:

0.567

Gnomad EAS exome

AF:

0.470

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.555

GnomAD4 exome

AF:

0.572

AC:

833938

AN:

1456968

Hom.:

241569

Cov.:

AF XY:

0.568

AC XY:

411764

AN XY:

724462

show subpopulations

African (AFR)

AF:

0.802

AC:

26595

AN:

33170

American (AMR)

AF:

0.464

AC:

20207

AN:

43556

Ashkenazi Jewish (ASJ)

AF:

0.562

AC:

14554

AN:

25916

East Asian (EAS)

AF:

0.444

AC:

17630

AN:

39670

South Asian (SAS)

AF:

0.435

AC:

36925

AN:

84936

European-Finnish (FIN)

AF:

0.548

AC:

29225

AN:

53328

Middle Eastern (MID)

AF:

0.564

AC:

3237

AN:

5742

European-Non Finnish (NFE)

AF:

0.586

AC:

650978

AN:

1110492

Other (OTH)

AF:

0.575

AC:

34587

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

20930

41859

62789

83718

104648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17858

35716

53574

71432

89290

<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:

0.626

AC:

95120

AN:

152038

Hom.:

30706

Cov.:

AF XY:

0.618

AC XY:

45903

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.791

AC:

32790

AN:

41470

American (AMR)

AF:

0.534

AC:

8152

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.560

AC:

1943

AN:

3468

East Asian (EAS)

AF:

0.464

AC:

2397

AN:

5162

South Asian (SAS)

AF:

0.443

AC:

2138

AN:

4826

European-Finnish (FIN)

AF:

0.539

AC:

5692

AN:

10566

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.587

AC:

39898

AN:

67962

Other (OTH)

AF:

0.625

AC:

1314

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1773

3545

5318

7090

8863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<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:

0.591

Hom.:

106946

Bravo

AF:

0.633

TwinsUK

AF:

0.598

AC:

2217

ALSPAC

AF:

0.579

AC:

2232

ESP6500AA

AF:

0.793

AC:

3493

ESP6500EA

AF:

0.595

AC:

5121

ExAC

AF:

0.552

AC:

67071

Asia WGS

AF:

0.506

AC:

1760

AN:

3478

EpiCase

AF:

0.590

EpiControl

AF:

0.588

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 -

not provided

Benign:3

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.046

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.037

MetaRNN

Benign

8.8e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.14

PhyloP100

1.5

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.20

REVEL

Benign

0.089

Sift

Benign

1.0

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.023

MPC

0.18

ClinPred

0.0013

GERP RS

4.6

Varity_R

0.081

gMVP

0.20

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

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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