11-108331553-ATAATG-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong
The NM_000051.4(ATM):c.7629_7629+4del variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N2542N) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 splice_donor, coding_sequence
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7629_7629+4del | splice_donor_variant, coding_sequence_variant | 51/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7629_7629+4del | splice_donor_variant, coding_sequence_variant | 51/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250372Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135384
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458648Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 725506
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 27, 2023 | Variant summary: ATM c.7629_7629+4delTGTAA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon skipping (Laake_2000). The variant allele was found at a frequency of 4e-06 in 250372 control chromosomes (gnomAD). c.7629_7629+4delTGTAA has been reported in the literature in a family affected with Ataxia-Telangiectasia with another pathogenic variant in trans (Laake_2000). The following publication has been ascertained in the context of this evaluation (PMID: 10980530). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Using RNA studies, this variant has been reported to result in an in-frame deletion of 38 amino acids in exon 53 (PMID: 10980530). However, specific data was not shown. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the canonical splice site is present in gnomAD (v2) at a frequency of 0.000004 (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 – Other splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The c.7629+1G>A and c.7629+2T>C canonical splice site variants have been classified as likely pathogenic in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 4 individuals with ataxia-telangiectasia (ClinVar, PMID: 10980530). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 232873). Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 10980530). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs751497695, gnomAD 0.0009%). This sequence change affects a splice site in intron 51 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 10, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2024 | The c.7629_7629+4delTGTAA pathogenic mutation spans the boundary of coding exon 50 and intron 50 of the ATM gene. This mutation results from a deletion of five nucleotides at positions 7629 to 7629+4. In one study, this mutation was detected and confirmed to be in trans with a second pathogenic ATM mutation in an ataxia-telangiectasia (AT) patient. mRNA analysis confirmed that this mutation causes complete skipping of coding exon 50, which is predicted to lead to the in-frame deletion of 38 amino acids at codons 2506 to 2543 (Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 08, 2021 | This variant causes a deletion of 5 nucleotides in the exon 51 and intron 51 junction of the ATM gene. RNA extracted from carrier-derived cells have shown that the variant leads to the skipping of exon 51 (also know as exon 53 in the literature), which is expected to result in an in-frame deletion of 38 amino acids (PMID: 10980530). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in an individual affected with ataxia telangiectasia (PMID: 10980530). This variant has been identified in 1/250372 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. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 31, 2024 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at