11-108284229-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.3749C>T​(p.Ser1250Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. S1250P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.32
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.3749C>T p.Ser1250Phe missense_variant, splice_region_variant Exon 26 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.3749C>T p.Ser1250Phe missense_variant, splice_region_variant Exon 26 of 63 NM_000051.4 ENSP00000501606.1 Q13315

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

Ataxia-telangiectasia syndrome Uncertain:1
Apr 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1250 of the ATM protein (p.Ser1250Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;T;T
Eigen
Uncertain
0.64
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;.
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.69
D;D;D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Uncertain
2.8
.;M;M
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.3
D;D;D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.87, 0.88
MutPred
0.34
Gain of methylation at K1253 (P = 0.1561);Gain of methylation at K1253 (P = 0.1561);Gain of methylation at K1253 (P = 0.1561);
MVP
0.93
MPC
0.22
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.55
gMVP
0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-108154956; API