GeneBe

rs1555066242

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting

The NM_000051.4(ATM):​c.501_503delGTT​(p.Leu167del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000714 in 1,400,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L167L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ATM
NM_000051.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.59

Publications

0 publications found
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]
ATM Gene-Disease associations (from GenCC):
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
  • ataxia telangiectasia
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
  • prostate cancer
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • familial ovarian cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • gastric carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 46 uncertain in NM_000051.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000051.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.501_503delGTT p.Leu167del disruptive_inframe_deletion Exon 6 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.501_503delGTT p.Leu167del disruptive_inframe_deletion Exon 6 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
7.14e-7
AC:
1
AN:
1400704
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
692680
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31050
American (AMR)
AF:
0.00
AC:
0
AN:
34832
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24962
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37286
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77340
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50694
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5562
European-Non Finnish (NFE)
AF:
9.25e-7
AC:
1
AN:
1081220
Other (OTH)
AF:
0.00
AC:
0
AN:
57758
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1
Jan 25, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant, c.501_503del, results in the deletion of 1 amino acid(s) of the ATM protein (p.Leu167del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 453552). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
6.6

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

Other links and lift over

dbSNP: rs1555066242; hg19: chr11-108114681; API