11-108293313-G-T
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000051.4(ATM):c.4612G>T(p.Val1538Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1538A) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ATM
NM_000051.4 missense, splice_region
NM_000051.4 missense, splice_region
Scores
10
8
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.67
Publications
2 publications found
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]
ATM Gene-Disease associations (from GenCC):
- ATM-related cancer predispositionInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
Variant 11-108293313-G-T is Pathogenic according to our data. Variant chr11-108293313-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 524317.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | MANE Select | c.4612G>T | p.Val1538Leu | missense splice_region | Exon 31 of 63 | ENSP00000501606.1 | Q13315 | ||
| ATM | TSL:1 | c.4612G>T | p.Val1538Leu | missense splice_region | Exon 32 of 64 | ENSP00000388058.2 | Q13315 | ||
| ATM | TSL:1 | c.4437-1614G>T | intron | N/A | ENSP00000434327.3 | H0YDU7 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1358702Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 677824
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1358702
Hom.:
Cov.:
25
AF XY:
AC XY:
0
AN XY:
677824
African (AFR)
AF:
AC:
0
AN:
30426
American (AMR)
AF:
AC:
0
AN:
38948
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
24590
East Asian (EAS)
AF:
AC:
0
AN:
38746
South Asian (SAS)
AF:
AC:
0
AN:
78634
European-Finnish (FIN)
AF:
AC:
0
AN:
51914
Middle Eastern (MID)
AF:
AC:
0
AN:
4976
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1033872
Other (OTH)
AF:
AC:
0
AN:
56596
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
-
2
-
Ataxia-telangiectasia syndrome (2)
2
-
-
Familial cancer of breast (2)
2
-
-
Hereditary cancer-predisposing syndrome (2)
-
2
-
not provided (2)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of methylation at K1536 (P = 0.0699)
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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