chr3-142459302-C-T

Position:

chr3-142459302-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 15/20 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:9

Conservation

PhyloP100: 0.0370

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATR. . Gene score misZ 4.3648 (greater than the threshold 3.09). Trascript score misZ 7.1274 (greater than threshold 3.09). GenCC has associacion of gene with sarcoma, Seckel syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Seckel syndrome 1.

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 id is 136470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142459302-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
ATR	NM_001184.4 linkuse as main transcript	c.7274G>A	p.Arg2425Gln	missense_variant	43/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9 linkuse as main transcript	c.7274G>A	p.Arg2425Gln	missense_variant	43/47	1	NM_001184.4	P1	Q13535-1

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

GnomAD3 exomes

AF:

0.131

AC:

32811

AN:

251230

Hom.:

2377

AF XY:

0.131

AC XY:

17833

AN XY:

135798

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 SAS exome

AF:

0.0957

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

Gnomad4 AFR exome

AF:

0.0736

Gnomad4 AMR exome

AF:

0.101

Gnomad4 ASJ exome

AF:

0.0794

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.167

Gnomad4 NFE exome

AF:

0.159

Gnomad4 OTH exome

AF:

0.138

GnomAD4 genome

AF:

0.127

AC:

19375

AN:

152120

Hom.:

1344

Cov.:

AF XY:

0.125

AC XY:

9319

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0808

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.0845

Gnomad4 EAS

AF:

0.101

Gnomad4 SAS

AF:

0.0989

Gnomad4 FIN

AF:

0.163

Gnomad4 NFE

AF:

0.160

Gnomad4 OTH

AF:

0.137

Alfa

AF:

0.148

Hom.:

4225

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	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

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Seckel syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

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

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

MutationTaster

Benign

1.0

P;P

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

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