NM_000051.4:c.8432dupA
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.8432dupA(p.Ser2812ValfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000275 in 1,456,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K2811K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ATM
NM_000051.4 frameshift
NM_000051.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.49
Publications
20 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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108345749-C-CA is Pathogenic according to our data. Variant chr11-108345749-C-CA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 187124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.8432dupA | p.Ser2812ValfsTer3 | frameshift | Exon 58 of 63 | NP_000042.3 | ||
| ATM | NM_001351834.2 | c.8432dupA | p.Ser2812ValfsTer3 | frameshift | Exon 59 of 64 | NP_001338763.1 | Q13315 | ||
| C11orf65 | NM_001330368.2 | c.641-36679dupT | intron | N/A | NP_001317297.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.8432dupA | p.Ser2812ValfsTer3 | frameshift | Exon 58 of 63 | ENSP00000501606.1 | Q13315 | |
| ATM | ENST00000452508.7 | TSL:1 | c.8432dupA | p.Ser2812ValfsTer3 | frameshift | Exon 59 of 64 | ENSP00000388058.2 | Q13315 | |
| C11orf65 | ENST00000615746.4 | TSL:1 | c.*1196+9165dupT | intron | N/A | ENSP00000483537.1 | Q8NCR3-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1456942Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 724830 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
1456942
Hom.:
Cov.:
30
AF XY:
AC XY:
2
AN XY:
724830
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33272
American (AMR)
AF:
AC:
0
AN:
44518
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26062
East Asian (EAS)
AF:
AC:
0
AN:
39578
South Asian (SAS)
AF:
AC:
0
AN:
85678
European-Finnish (FIN)
AF:
AC:
0
AN:
53302
Middle Eastern (MID)
AF:
AC:
0
AN:
5720
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1108670
Other (OTH)
AF:
AC:
0
AN:
60142
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00215951), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.338
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
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55-60
60-65
65-70
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Hereditary cancer-predisposing syndrome (3)
3
-
-
not provided (3)
1
-
-
Ataxia-telangiectasia syndrome (1)
1
-
-
Familial cancer of breast (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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