rs767533596
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.8435_8436delCT(p.Ser2812PhefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S2812S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ATM
NM_000051.4 frameshift
NM_000051.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.06
Publications
3 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 11-108345757-GTC-G is Pathogenic according to our data. Variant chr11-108345757-GTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 407667.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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.8435_8436delCT | p.Ser2812PhefsTer2 | frameshift | Exon 58 of 63 | NP_000042.3 | ||
| ATM | NM_001351834.2 | c.8435_8436delCT | p.Ser2812PhefsTer2 | frameshift | Exon 59 of 64 | NP_001338763.1 | |||
| C11orf65 | NM_001330368.2 | c.641-36688_641-36687delGA | intron | N/A | NP_001317297.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.8435_8436delCT | p.Ser2812PhefsTer2 | frameshift | Exon 58 of 63 | ENSP00000501606.1 | ||
| ATM | ENST00000452508.7 | TSL:1 | c.8435_8436delCT | p.Ser2812PhefsTer2 | frameshift | Exon 59 of 64 | ENSP00000388058.2 | ||
| ATM | ENST00000527805.6 | TSL:1 | n.*3499_*3500delCT | non_coding_transcript_exon | Exon 56 of 61 | ENSP00000435747.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 250672 AF XY: 0.00000738 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
250672
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459052Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 725794 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1459052
Hom.:
AF XY:
AC XY:
0
AN XY:
725794
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33346
American (AMR)
AF:
AC:
0
AN:
44588
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26078
East Asian (EAS)
AF:
AC:
2
AN:
39592
South Asian (SAS)
AF:
AC:
0
AN:
85840
European-Finnish (FIN)
AF:
AC:
0
AN:
53328
Middle Eastern (MID)
AF:
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1110316
Other (OTH)
AF:
AC:
0
AN:
60224
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
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2
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0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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<30
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Familial cancer of breast (2)
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
Ataxia-telangiectasia syndrome (1)
1
-
-
not provided (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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