chr3-142449471-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001184.4(ATR):​c.7893C>G​(p.Asn2631Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ATR
NM_001184.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.249
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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=0.13515308).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATRNM_001184.4 linkuse as main transcriptc.7893C>G p.Asn2631Lys missense_variant 47/47 ENST00000350721.9 NP_001175.2
ATRNM_001354579.2 linkuse as main transcriptc.7701C>G p.Asn2567Lys missense_variant 46/46 NP_001341508.1
ATRXM_011512924.2 linkuse as main transcriptc.7899C>G p.Asn2633Lys missense_variant 47/47 XP_011511226.1
ATRXM_011512925.2 linkuse as main transcriptc.7707C>G p.Asn2569Lys missense_variant 46/46 XP_011511227.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATRENST00000350721.9 linkuse as main transcriptc.7893C>G p.Asn2631Lys missense_variant 47/471 NM_001184.4 ENSP00000343741 P1Q13535-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

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 submitterclinical testingAmbry GeneticsMay 05, 2023The p.N2631K variant (also known as c.7893C>G), located in coding exon 47 of the ATR gene, results from a C to G substitution at nucleotide position 7893. The asparagine at codon 2631 is replaced by lysine, an amino acid with 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
0.11
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
9.0
DANN
Uncertain
0.98
DEOGEN2
Benign
0.13
T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.0061
T
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.93
N
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.24
Sift
Benign
0.26
T
Sift4G
Benign
0.72
T
Polyphen
0.013
B
Vest4
0.26
MutPred
0.47
Gain of ubiquitination at N2631 (P = 0.0325);
MVP
0.64
MPC
0.74
ClinPred
0.48
T
GERP RS
2.8
Varity_R
0.23
gMVP
0.44

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.

Other links and lift over

dbSNP: rs2070730666; hg19: chr3-142168313; API