Variant 3-142449479-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001184.4(ATR):c.7885G>A(p.Asp2629Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2629E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.39357704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATR	NM_001184.4 linkuse as main transcript	c.7885G>A	p.Asp2629Asn	missense_variant	47/47	ENST00000350721.9
ATR	NM_001354579.2 linkuse as main transcript	c.7693G>A	p.Asp2565Asn	missense_variant	46/46
ATR	XM_011512924.2 linkuse as main transcript	c.7891G>A	p.Asp2631Asn	missense_variant	47/47
ATR	XM_011512925.2 linkuse as main transcript	c.7699G>A	p.Asp2567Asn	missense_variant	46/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9 linkuse as main transcript	c.7885G>A	p.Asp2629Asn	missense_variant	47/47	1	NM_001184.4	P1	Q13535-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251422

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461092

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2022

The p.D2629N variant (also known as c.7885G>A), located in coding exon 47 of the ATR gene, results from a G to A substitution at nucleotide position 7885. The aspartic acid at codon 2629 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.035

MetaRNN

Benign

0.39

MetaSVM

Uncertain

-0.049

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.77

REVEL

Uncertain

0.36

Sift

Benign

0.38

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.29

MutPred

0.58

Gain of catalytic residue at T2628 (P = 0.239);

MVP

0.82

MPC

0.84

ClinPred

0.45

GERP RS

5.5

Varity_R

0.25

gMVP

0.73

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