NM_001184.4:c.992A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001184.4(ATR):c.992A>G(p.Asp331Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,116 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D331D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 0.159

Publications

5 publications found

Variant links:

COSMIC-nc: COSV104670864

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061575174).

BP6

Variant 3-142562410-T-C is Benign according to our data. Variant chr3-142562410-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379486.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.992A>G	p.Asp331Gly	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.992A>G	p.Asp331Gly	missense_variant	Exon 4 of 47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00140

AC:

351

AN:

251392

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00845

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00129

AC:

1884

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

908

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33476

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00910

AC:

486

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00115

AC:

1274

AN:

1111982

Other (OTH)

AF:

0.00123

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00112

AC:

171

AN:

152276

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41560

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00687

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68008

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000797

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00128

AC:

156

EpiCase

AF:

0.000818

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

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

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATR: PP2, BP4, BS2 -

not specified

Benign:2

Sep 01, 2016

GeneDx

Significance:Likely 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. -

Sep 11, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seckel syndrome 1

Benign:2

Feb 08, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases

Uncertain:1

Apr 20, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.992A>G (p.D331G) alteration is located in exon 4 (coding exon 4) of the ATR gene. This alteration results from a A to G substitution at nucleotide position 992, causing the aspartic acid (D) at amino acid position 331 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial cancer of breast

Uncertain:1

Apr 08, 2020

Center of Medical Genetics and Primary Health Care

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

ACMG Guidelines 2015 criteria PP4 Pathogenic Supporting: The patient has family history of breast cancer BS1 Benign Strong: GnomAD exomes allele frequency = 0.0014 > 0.000388 derived from the 207 clinically reported variants in gene ATR of which 6 PATH, 97 VUS and 104 BEN. BP1 Benign Supporting: 32 out of 32 non-VUS missense variants in gene ATR are BEN = 100.0% > threshold of 51.0%, and 104 out of 207 clinically reported variants in gene ATR are BEN = 50.2% > threshold of 24.0%. BP4 Benign Supporting: 10 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs no pathogenic predictions and the position is not conserved. Therefore, there is insufficient information and this variant was classified as a Variant of Unknown Significance. -

ATR-related disorder

Benign:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Benign:1

Feb 08, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.074

T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.67

T;.

M_CAP

Benign

0.0080

MetaRNN

Benign

0.0062

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PhyloP100

0.16

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.18

Sift

Benign

0.49

T;T

Sift4G

Benign

0.58

T;.

Polyphen

0.0

B;.

Vest4

0.11

MVP

0.74

MPC

0.21

ClinPred

0.0027

GERP RS

1.8

Varity_R

0.15

gMVP

0.20

Mutation Taster

=100/0

polymorphism

(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