chr11-108329256-A-G
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000051.4(ATM):c.7307+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,593,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ATM
NM_000051.4 intron
NM_000051.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.01
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 11-108329256-A-G is Benign according to our data. Variant chr11-108329256-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420710.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7307+18A>G | intron_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7307+18A>G | intron_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.94e-7 AC: 1AN: 1441720Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 718060
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2016 | This variant is denoted ATM c.7307+18A>G or IVS49+18A>G and consists of a A>G nucleotide substitution at the +18 position of intron 49 of the ATM gene. Multiple in silico models predict this variant to create a cryptic splice donor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM c.7307+18A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether ATM c.7307+18A>G is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2014 | The c.7307+18A>G intronic variant results from an A to G substitution 18 nucleotides after coding exon 48 in the ATM gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. This nucleotide position is not well conserved in available vertebrate species. Using the ESEfinder splice site prediction tool, this alteration does not have any significant effect on the native splice donor site. Using the BDGP splice site prediction tool, this alteration does not have any significant effect on the native splice donor site; however it predicts the creation of a new alternate splice acceptor splice site. Direct evidence of any impact on splicing is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.7307+18A>G remains unclear. - |
Ataxia-telangiectasia syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at