rs1555126163

Positions:

• chr11-108333885-G-A
• chr11-108333885-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PM2 PP3_Strong PP5

The NM_000051.4(ATM):​c.7928-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.3, offset of -34, new splice context is: ccttcaatgctgttcctcAGttt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108333885-G-A is Pathogenic according to our data. Variant chr11-108333885-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 482651.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7928-1G>A		splice_acceptor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7928-1G>A		splice_acceptor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2023

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with ataxia telangiectasia who also carried two different truncating ATM variants, one on the opposite allele (in trans) and the other on the same allele (in cis) (Cavalieri et al., 2008); This variant is associated with the following publications: (PMID: 16199547, 23807571, 25614872, 17910737) -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change affects an acceptor splice site in intron 53 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 and insertion of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia, however the variant was on the same chromosome as one of two other truncating variants detected (PMID: 17910737). ClinVar contains an entry for this variant (Variation ID: 482651). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 54 (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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2023

The c.7928-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 53 of the ATM gene. This alteration has been previously observed in an individual with ataxia-telangiectasia. This individual had three ATM alterations; the c.7928-1G>A alteration was found to be in cis with a frameshift alteration and in trans with a nonsense alteration via parental testing (Cavalieri S et al. Ann. Hum. Genet., 2008 Jan;72:10-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555126163; hg19: chr11-108204612; COSMIC: COSV53763777; COSMIC: COSV53763777;