rs587781950

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000051.4(ATM):​c.4198A>C​(p.Lys1400Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. K1400T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ATM
NM_000051.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89
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.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000051.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2872098).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATMNM_000051.4 linkuse as main transcriptc.4198A>C p.Lys1400Gln missense_variant 28/63 ENST00000675843.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.4198A>C p.Lys1400Gln missense_variant 28/63 NM_000051.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 02, 2019This missense variant replaces lysine with glutamine at codon 1400 of the ATM protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.038
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.086
T;T;T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.85
T;.;T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.29
T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Uncertain
2.7
M;M;.
MutationTaster
Benign
0.95
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.1
N;N;.
REVEL
Benign
0.23
Sift
Benign
0.045
D;D;.
Sift4G
Uncertain
0.060
T;T;T
Polyphen
0.35
B;B;.
Vest4
0.67
MutPred
0.30
Gain of ubiquitination at K1398 (P = 0.0408);Gain of ubiquitination at K1398 (P = 0.0408);.;
MVP
0.83
MPC
0.23
ClinPred
0.75
D
GERP RS
5.4
Varity_R
0.27
gMVP
0.26

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: rs587781950; hg19: chr11-108159792; API