rs876660661
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_000051.4(ATM):c.172G>A(p.Asp58Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D58Y) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 8.59
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 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-108227875-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 233820.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, Pathogenic=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.172G>A | p.Asp58Asn | missense_variant | 3/63 | ENST00000675843.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.172G>A | p.Asp58Asn | missense_variant | 3/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. ClinVar contains an entry for this variant (Variation ID: 1351284). 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 58 of the ATM protein (p.Asp58Asn). - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2020 | The p.D58N variant (also known as c.172G>A), located in coding exon 2 of the ATM gene, results from a G to A substitution at nucleotide position 172. The aspartic acid at codon 58 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 08, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T;T;T;.;T;T;T;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.;.;.;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;.;.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;D;D;.;N;.;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;.;D;.;.;.;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;.;.;.;D;D
Polyphen
1.0
.;D;.;.;.;D;D;D;D;D;.
Vest4
0.62, 0.72, 0.71, 0.73
MutPred
Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);Gain of MoRF binding (P = 0.0432);
MVP
MPC
0.57
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.