rs864622490
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.3663G>A(p.Trp1221*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,589,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3663G>A | p.Trp1221* | stop_gained | Exon 25 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250896Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135640
GnomAD4 exome AF: 0.00000209 AC: 3AN: 1437796Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1AN XY: 716880
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Trp1221*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348, 22071889). ClinVar contains an entry for this variant (Variation ID: 220358). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: ATM c.3663G>A (p.Trp1221X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Leu1238fsX6 and p.Arg1466X). The variant was absent in 120132 control chromosomes. The c.3663G>A variant has been reported in the literature in several compound heterozygous individuals affected with Ataxia-Telangiectasia. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed with a second pathogenic ATM variant in multiple unrelated individuals with ataxia-telangiectasia (Teraoka 1999, Bernstein 2003, Jacquemin 2012, Hoche 2014); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 10330348, 12673797, 25037873, 16461462, 22071889, 25525159, 12815592, 32756499, 35095854) -
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Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 25 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 10330348, 12673797, 22071889, 25037873). This variant has also been reported in an individual affected with breast cancer (PMID: 32756499). This variant has been identified in 2/282288 chromosomes 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 Pathogenic. -
The p.W1221* pathogenic mutation (also known as c.3663G>A), located in coding exon 24 of the ATM gene, results from a G to A substitution at nucleotide position 3663. This changes the amino acid from a tryptophan to a stop codon within coding exon 24. This pathogenic mutation has been reported in multiple ataxia-telangiectasia patients (Teraoka SN et al. Am. J. Hum. Genet., 1999 Jun;64:1617-31; Jacquemin V et al. Eur. J. Hum. Genet., 2012 Mar;20:305-12; Hoche F et al. Pediatr. Neurol., 2014 Sep;51:297-310; Micol RJ et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9.e1). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1Other:1
Variant interpreted as Pathogenic and reported on 07-06-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at