rs150008448
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_001184.4(ATR):āc.992A>Gā(p.Asp331Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,116 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D331D) has been classified as Likely benign.
Frequency
Consequence
NM_001184.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATR | NM_001184.4 | c.992A>G | p.Asp331Gly | missense_variant | 4/47 | ENST00000350721.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATR | ENST00000350721.9 | c.992A>G | p.Asp331Gly | missense_variant | 4/47 | 1 | NM_001184.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00112 AC: 171AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00140 AC: 351AN: 251392Hom.: 1 AF XY: 0.00130 AC XY: 177AN XY: 135880
GnomAD4 exome AF: 0.00129 AC: 1884AN: 1461840Hom.: 3 Cov.: 30 AF XY: 0.00125 AC XY: 908AN XY: 727216
GnomAD4 genome ? AF: 0.00112 AC: 171AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93AN XY: 74470
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ATR: PP2, BP4, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 17, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2016 | 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 | Genetic Services Laboratory, University of Chicago | Sep 11, 2020 | - - |
Seckel syndrome 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2021 | The c.992A>G (p.D331G) alteration is located in exon 4 (coding exon 4) of the ATR gene. This alteration results from a A to G substitution at nucleotide position 992, causing the aspartic acid (D) at amino acid position 331 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial cancer of breast Uncertain:1
Uncertain significance, no assertion criteria provided | research | Center of Medical Genetics and Primary Health Care | Apr 08, 2020 | ACMG Guidelines 2015 criteria PP4 Pathogenic Supporting: The patient has family history of breast cancer BS1 Benign Strong: GnomAD exomes allele frequency = 0.0014 > 0.000388 derived from the 207 clinically reported variants in gene ATR of which 6 PATH, 97 VUS and 104 BEN. BP1 Benign Supporting: 32 out of 32 non-VUS missense variants in gene ATR are BEN = 100.0% > threshold of 51.0%, and 104 out of 207 clinically reported variants in gene ATR are BEN = 50.2% > threshold of 24.0%. BP4 Benign Supporting: 10 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs no pathogenic predictions and the position is not conserved. Therefore, there is insufficient information and this variant was classified as a Variant of Unknown Significance. - |
Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at