rs878853495

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000051.4(ATM):​c.2466+2T>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

ATM
NM_000051.4 splice_donor

Scores

3
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.50
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009704503 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of 4, new splice context is: aaaGTatgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108259077-T-A is Pathogenic according to our data. Variant chr11-108259077-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkuse as main transcriptc.2466+2T>A splice_donor_variant ENST00000675843.1 NP_000042.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.2466+2T>A splice_donor_variant NM_000051.4 ENSP00000501606 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The splice donor variant c.2466+2T>A in ATM (NM_000051.4) has been reported to ClinVar as Likely Pathogenic. It has not been reported previously in affected individuals. The c.2466+2T>A variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice site and hence is predicted to cause loss of function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 06, 2015This variant has not been reported in the literature. Truncating variants in ATM are known to be pathogenic (PMID: 10817650, 19781682), and donor splice site variants are typically pathogenic (PMID: 16199547). In the absence of supporting functional or genetic data, this variant has been classified as Likely Pathogenic. This sequence change affects a donor splice site in intron 16. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
29
DANN
Benign
0.96
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.95
D
MutationTaster
Benign
1.0
D;D
GERP RS
4.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.95
Position offset: -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: rs878853495; hg19: chr11-108129804; API