rs755860432
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000051.4(ATM):c.876G>A(p.Pro292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,610,766 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P292P) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.876G>A | p.Pro292= | synonymous_variant | 7/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.876G>A | p.Pro292= | synonymous_variant | 7/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000524 AC: 13AN: 248152Hom.: 0 AF XY: 0.0000669 AC XY: 9AN XY: 134624
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1458694Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 725822
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74270
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2023 | - - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Pro292= variant was identified in the literature however the frequency of this variant in an affected population was not provided (Decker 2017). The variant was also identified in the following databases: dbSNP (ID: rs755860432) as "With Likely benign allele", ClinVar (2x likely benign, 1x benign), and Clinvitae (2x likely benign, 1x benign). The variant was not identified in Cosmic, MutDB, or LOVD 3.0. The variant was identified in control databases in 13 of 243644 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Latino in 5 of 33486 chromosomes (freq: 0.0001), European in 1 of 111146 chromosomes (freq: 0.000009), Ashkenazi Jewish in 2 of 9828 chromosomes (freq: 0.0002), East Asian in 1 of 17192 chromosomes (freq: 0.00006), and South Asian in 4 of 30758 chromosomes (freq: 0.0001). The variant was not observed in the African, Other, or Finnish populations. The p.Pro292 residue is conserved across mammals and other organisms, however it is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In our lab this variant was observed with a co-occurring pathogenic BRCA1 variant c.5161C>T, increasing the likelihood that the p.Pro292= variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | ATM: BP4, BP7 - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2015 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 25, 2017 | - - |
Ataxia-telangiectasia syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 23, 2024 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at