rs778890679
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):c.1487G>A(p.Ser496Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000142 in 1,614,040 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 (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.1487G>A | p.Ser496Asn | missense_variant | Exon 10 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461860Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8AN XY: 727226
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
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This missense variant replaces serine with asparagine at codon 496 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
PM2_Supporting, BP4 c.1487G>A, located in exon 10 of the ATM gene, is predicted to result in the substitution of serine by asparagine at codon 496, p.(Ser496Asn). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.083) suggests that it does not affect the protein function (BP4). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been reported 5 times in ClinVar as of uncertain significance, and has not been reported in the LOVD. Based on currently available information, the variant c.1487G>A should be considered an uncertain significance variant according to ACMG Classification Rules Specified for ATM v1.1. -
The p.S496N variant (also known as c.1487G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1487. The serine at codon 496 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. -
Ataxia-telangiectasia syndrome Uncertain:1
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 496 of the ATM protein (p.Ser496Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 234029). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
not provided Uncertain:1
The ATM p.Ser496Asn variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in dbSNP (ID: rs778890679) as “With Uncertain Significance allele”. In ClinVar, the variant was classified as a variant uncertain significance by Ambry Genetics and Invitae for Ataxia-telangiectasia syndrome and Hereditary cancer-predisposing syndrome. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser496 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at