rs1555152058
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5
The NM_000051.4(ATM):c.9145_9146del(p.Phe3049ProfsTer13) variant causes a frameshift 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L3048L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
ATM
NM_000051.4 frameshift
NM_000051.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.64
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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 3123 codons.
PP5
?
Variant 11-108365479-CTT-C is Pathogenic according to our data. Variant chr11-108365479-CTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 524412.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.9145_9146del | p.Phe3049ProfsTer13 | frameshift_variant | 63/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.9145_9146del | p.Phe3049ProfsTer13 | frameshift_variant | 63/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 06, 2024 | This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650, 16266405, 25614872, 15039971, 21965147]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 08, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 2 nucleotides in exon 63 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2020 | The c.9145_9146delTT variant, located in coding exon 62 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 9145 to 9146, causing a translational frameshift with a predicted alternate stop codon (p.F3049Pfs*13). This alteration has been reported in a compound heterozygous state in a cohort of families with ataxia telangiectasia (A-T) in the United States and Canada (Li A et al. Am. J. Med. Genet., 2000 May;92:170-7). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of ATM, is not expected to trigger nonsense-mediated mRNA decay, and results in the alteration of the last 8 amino acids and elongation of the protein by 4 amino acids. The exact functional impact of these altered/inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ataxia-telangiectasia syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change results in a frameshift in the ATM gene (p.Phe3049Profs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the ATM protein and extend the protein by 4 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with ataxia-telangiectasia (PMID: 10817650). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 524412). This variant disrupts the FATC domain, which spans the last 33 amino acids of the ATM protein and is required for ATM kinase activity in response to DNA damage (PMID: 19781682, 16603769). While functional studies have not been performed to directly test the effect of this variant on ATM protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 23
Find out detailed SpliceAI scores and Pangolin per-transcript scores at