rs771117943
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000051.4(ATM):c.4776+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000051.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4776+1G>A | splice_donor_variant | ENST00000675843.1 | NP_000042.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4776+1G>A | splice_donor_variant | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1455982Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4AN XY: 724706
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of 31, but is expected to preserve the integrity of the reading-frame (PMID: 31050087). Experimental studies have shown that disruption of this splice site affects ATM function (PMID: 2491181, 9497252). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1742995). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 9497252, 12815592). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2020 | The c.4776+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 30 of the ATM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Several alterations at this donor site have been identified in individuals with ataxia-telangiectasia (Mitui M et al. Hum. Mutat. 2003; 22:43-50; Gilad S et al. Am. J. Hum. Genet. 1998; 62:551-61; Teraoka SN et al. Am. J. Hum. Genet. 1999; 64:1617-31) and have also been shown to cause abnormal splicing (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.