3-142459276-G-C

Position:

chr3-142459276-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001184.4(ATR):c.7300C>G(p.Pro2434Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00225 in 1,613,982 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 32 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 31 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.65

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:

ATR (HGNC:):

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=0.007993221).

BP6

Variant 3-142459276-G-C is Benign according to our data. Variant chr3-142459276-G-C is described in ClinVar as [Benign]. Clinvar id is 158003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1765/152286) while in subpopulation AFR AF= 0.041 (1703/41570). AF 95% confidence interval is 0.0393. There are 32 homozygotes in gnomad4. There are 830 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4 linkuse as main transcript	c.7300C>G	p.Pro2434Ala	missense_variant	43/47	ENST00000350721.9	NP_001175.2	Q13535-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 linkuse as main transcript	c.7300C>G	p.Pro2434Ala	missense_variant	43/47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1764

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00322

AC:

808

AN:

251314

Hom.:

AF XY:

0.00238

AC XY:

323

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0430

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00128

AC:

1866

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

813

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0431

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.0116

AC:

1765

AN:

152286

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

830

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0410

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0386

AC:

170

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00382

AC:

464

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2015	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. -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Benign:2

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

0.081

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.52

Sift

Benign

0.033

Sift4G

Benign

0.092

Polyphen

1.0

Vest4

0.51

MVP

0.78

MPC

0.69

ClinPred

0.095

GERP RS

3.7

Varity_R

0.63

gMVP

0.49

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