11-108295029-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000051.4(ATM):​c.4879C>A​(p.Gln1627Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.76
Variant links:
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkuse as main transcriptc.4879C>A p.Gln1627Lys missense_variant 32/63 ENST00000675843.1 NP_000042.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.4879C>A p.Gln1627Lys missense_variant 32/63 NM_000051.4 ENSP00000501606 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461638
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727134
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 21, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 453542). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with lysine at codon 1627 of the ATM protein (p.Gln1627Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 08, 2023The p.Q1627K variant (also known as c.4879C>A), located in coding exon 31 of the ATM gene, results from a C to A substitution at nucleotide position 4879. The glutamine at codon 1627 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
0.10
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.75
T;.
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Uncertain
2.6
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.2
N;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.021
D;D
Sift4G
Uncertain
0.020
D;D
Polyphen
0.99
D;D
Vest4
0.78
MutPred
0.43
Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP
0.95
MPC
0.37
ClinPred
0.95
D
GERP RS
5.5
Varity_R
0.41
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
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: rs886039592; hg19: chr11-108165756; API