3-142555928-T-C

Position:

chr3-142555928-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001184.4(ATR):c.2290A>G(p.Lys764Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00459 in 1,612,994 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 30 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 4.14

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009344518).

BP6

Variant 3-142555928-T-C is Benign according to our data. Variant chr3-142555928-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157970.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=3}. Variant chr3-142555928-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.2290A>G	p.Lys764Glu	missense_variant	10/47	ENST00000350721.9	NP_001175.2	Q13535-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 link	c.2290A>G	p.Lys764Glu	missense_variant	10/47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00507

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00329

AC:

823

AN:

250116

Hom.:

AF XY:

0.00317

AC XY:

428

AN XY:

135104

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00253

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000864

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00410

GnomAD4 exome

AF:

0.00472

AC:

6889

AN:

1460704

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

3233

AN XY:

726554

show subpopulations

Gnomad4 AFR exome

AF:

0.000599

Gnomad4 AMR exome

AF:

0.00234

Gnomad4 ASJ exome

AF:

0.00670

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000769

Gnomad4 FIN exome

AF:

0.00210

Gnomad4 NFE exome

AF:

0.00542

Gnomad4 OTH exome

AF:

0.00618

GnomAD4 genome

AF:

0.00337

AC:

513

AN:

152290

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00507

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00459

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00325

AC:

395

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00567

EpiControl

AF:

0.00551

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATR p.Lys764Glu variant was identified in 1 of 100 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and was not identified in 72 control chromosomes from healthy individuals (Durocher_2006_17010193). In Wang et al., the variant was also identified in 1/48 breast cancer tumours (Wang_2008_PMID: 18281469). The variant was also identified in the following databases: dbSNP (ID: rs77208665) and was found in ClinVar (where it was reported as likely benign and a VUS for Seckel syndrome 1), Clinvitae, Cosmic (with a FATHMM prediction of Pathogenic (score=0.95)), MutDB and LOVD 3.0. The variant was identified in control databases in 902 of 281492 chromosomes (5 homozygous) at a frequency of 0.003204 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 64 of 10326 chromosomes (freq: 0.006198), European (non-Finnish) in 630 of 128766 chromosomes (freq: 0.004893), other in 26 of 7180 chromosomes (freq: 0.003621), Latino in 89 of 35200 chromosomes (freq: 0.002528), European (Finnish) in 53 of 25088 chromosomes (freq: 0.002113), South Asian in 26 of 30084 chromosomes (freq: 0.000864) and African in 14 of 24956 chromosomes (freq: 0.000561); it was not observed in the East Asian populations. The p.Lys764 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2019	This variant is associated with the following publications: (PMID: 28787443) -

Seckel syndrome 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Benign

-0.031

Eigen_PC

Benign

0.0053

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0093

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Benign

0.042

Sift4G

Uncertain

0.021

Polyphen

0.92

Vest4

0.62

MVP

0.79

MPC

0.53

ClinPred

0.011

GERP RS

4.2

Varity_R

0.36

gMVP

0.34

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