rs149008479
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_001184.4(ATR):c.3424A>G(p.Ser1142Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000901 in 1,613,320 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00055 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00094 ( 0 hom. )
Consequence
ATR
NM_001184.4 missense
NM_001184.4 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 5.11
Genes affected
ATR (HGNC:882): (ATR serine/threonine kinase) The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ATR
BP4
?
Computational evidence support a benign effect (MetaRNN=0.056938678).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATR | NM_001184.4 | c.3424A>G | p.Ser1142Gly | missense_variant | 17/47 | ENST00000350721.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATR | ENST00000350721.9 | c.3424A>G | p.Ser1142Gly | missense_variant | 17/47 | 1 | NM_001184.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000552 AC: 84AN: 152122Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000594 AC: 149AN: 250798Hom.: 0 AF XY: 0.000605 AC XY: 82AN XY: 135566
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GnomAD4 exome AF: 0.000938 AC: 1370AN: 1461080Hom.: 0 Cov.: 30 AF XY: 0.000890 AC XY: 647AN XY: 726844
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Seckel syndrome 1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 04, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2015 | A variant of unknown significance has been identified in the ATR gene. The S1142G variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The S1142G variant was not observed with any significant frequency in the 1000 Genomes Project and in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The S1142G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however Glycine has been seen at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1142 of the ATR protein (p.Ser1142Gly). This variant is present in population databases (rs149008479, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cancer (PMID: 15987455, 32522261). ClinVar contains an entry for this variant (Variation ID: 157977). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at