rs148590073

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):ā€‹c.370A>Gā€‹(p.Ile124Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,612,068 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 Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0020 ( 1 hom., cov: 33)
Exomes š‘“: 0.00021 ( 2 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

19

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.886
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005322814).
BP6
Variant 11-108235708-A-G is Benign according to our data. Variant chr11-108235708-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 127373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00196 (299/152344) while in subpopulation AFR AF= 0.00681 (283/41574). AF 95% confidence interval is 0.00615. There are 1 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkuse as main transcriptc.370A>G p.Ile124Val missense_variant 5/63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.370A>G p.Ile124Val missense_variant 5/63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.00196
AC:
299
AN:
152226
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00683
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.000593
AC:
149
AN:
251154
Hom.:
0
AF XY:
0.000420
AC XY:
57
AN XY:
135752
show subpopulations
Gnomad AFR exome
AF:
0.00720
Gnomad AMR exome
AF:
0.000492
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000206
AC:
301
AN:
1459724
Hom.:
2
Cov.:
30
AF XY:
0.000183
AC XY:
133
AN XY:
726316
show subpopulations
Gnomad4 AFR exome
AF:
0.00650
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000423
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.00196
AC:
299
AN:
152344
Hom.:
1
Cov.:
33
AF XY:
0.00184
AC XY:
137
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00681
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.000468
Hom.:
0
Bravo
AF:
0.00216
ESP6500AA
AF:
0.00795
AC:
35
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000750
AC:
91
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000296

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:8
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 31, 2021- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 14, 2021This variant is associated with the following publications: (PMID: 22952040, 11505391, 17333338, 19781682, 12673804, 25980754, 12552559) -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 30, 2019- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 30, 2019- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2024ATM: BP1, BP2, BP4, BS1 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not specified Benign:4
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 07, 2017Variant summary: The ATM c.370A>G (p.Ile124Val) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 93/126020 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.007634 (79/10348). This frequency is about 8 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This missense mutation has been observed in cancer patients without significant evidence for a causal role in disease (e.g. co-segregation data were not provided). In at least one ataxia-telangiectasia patient the variant co-occured with two other mutations predicted to be causative for ataxia-telangiectasia (Buzin_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, and most peer reviewed publications consider the variant a polymorphism. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 23, 2021- -
Ataxia-telangiectasia syndrome Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitterclinical testingCounsylJan 19, 2018- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submittercurationSema4, Sema4Sep 10, 2020- -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 04, 2015- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2018This 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. -
Familial cancer of breast Benign:2
Benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 19, 2024This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
5.3
DANN
Benign
0.52
DEOGEN2
Benign
0.032
.;T;.;T;T
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.71
T;T;T;.;T
M_CAP
Benign
0.0064
T
MetaRNN
Benign
0.0053
T;T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-1.4
.;N;.;N;.
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.050
N;N;.;N;.
REVEL
Benign
0.040
Sift
Benign
1.0
T;T;.;T;.
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0010
.;B;.;B;.
Vest4
0.089, 0.060, 0.081
MVP
0.58
MPC
0.10
ClinPred
0.0019
T
GERP RS
0.39
Varity_R
0.031
gMVP
0.095

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148590073; hg19: chr11-108106435; COSMIC: COSV104592208; COSMIC: COSV104592208; API