11-108243969-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000051.4(ATM):c.513C>T(p.Tyr171Tyr) variant causes a synonymous 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Failed GnomAD Quality Control
Consequence
ATM
NM_000051.4 synonymous
NM_000051.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.701
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;
PP5
Variant 11-108243969-C-T is Pathogenic according to our data. Variant chr11-108243969-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 802727.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr11-108243969-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.513C>T | p.Tyr171Tyr | synonymous_variant | Exon 6 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 148666Hom.: 0 Cov.: 32 FAILED QC
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GnomAD4 exome Cov.: 33
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GnomAD4 genome 0.00 AC: 0AN: 148666Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 72152
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2023 | This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 14695534). ClinVar contains an entry for this variant (Variation ID: 802727). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. This sequence change affects codon 171 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 29, 2022 | - - |
ATM-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 27, 2024 | The ATM c.513C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported as homozygous in an individual with ataxia telangiectasia (Table 1, Eng et al. 2004. PubMed ID: 14695534). Although this variant results in a silent protein change, it causes a splicing defect by activating a cryptic splice site that results in a premature termination codon (Eng et al. 2004. PubMed ID: 14695534). This variant has not been reported in a large population database, indicating this variant is rare. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/802727/). This variant is interpreted as likely pathogenic. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 6
DS_AL_spliceai
Position offset: -16
Find out detailed SpliceAI scores and Pangolin per-transcript scores at