rs537377433
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000051.4(ATM):c.4639A>G(p.Ile1547Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000255 in 1,570,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. I1547L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4639A>G | p.Ile1547Val | missense_variant | 31/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4639A>G | p.Ile1547Val | missense_variant | 31/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000818 AC: 2AN: 244454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132160
GnomAD4 exome AF: 0.00000212 AC: 3AN: 1418150Hom.: 0 Cov.: 28 AF XY: 0.00000141 AC XY: 1AN XY: 706978
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74426
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 453531). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is present in population databases (rs537377433, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1547 of the ATM protein (p.Ile1547Val). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2022 | The p.I1547V variant (also known as c.4639A>G), located in coding exon 30 of the ATM gene, results from an A to G substitution at nucleotide position 4639. The isoleucine at codon 1547 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well 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 | Jul 11, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at