11-108293478-G-T

Position:

• chr11-108293478-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.4776+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.58

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017882455 fraction of the gene. No cryptic splice site detected. Exon removal is inframe 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 11-108293478-G-T is Pathogenic according to our data. Variant chr11-108293478-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 478920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108293478-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4776+1G>T		splice_donor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4776+1G>T		splice_donor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455982 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 26, 2023	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs771117943, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 9497252, 12815592, 20840352, 31050087). ClinVar contains an entry for this variant (Variation ID: 478920). Experimental studies have shown that disruption of this splice site affects ATM function (PMID: 2491181, 9497252). Studies have shown that disruption of this splice site results in skipping of 31, but is expected to preserve the integrity of the reading-frame (PMID: 31050087). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 12, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2023	The c.4776+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 30 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This mutation has been seen in conjunction with another pathogenic ATM mutation in a 9 year old female with severe ataxia-telangiectasia (A-T) (Broccoletti T et al. Eur. J. Neurol. 2011 Apr;18:564-70). In another study, this alteration was identified with a missense ATM alteration in an individual with atypical A-T and was reported to cause skipping of coding exon 30 (Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 09, 2023	This variant causes a G to T nucleotide substitution at the +1 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing and is expected to result in a disrupted protein product. This variant has been reported in unknown phase with a pathogenic ATM variant, c.748C>T (p.Arg250Ter), in an individual affected with classic ataxia-telangiectasia (PMID: 20840352, 22763152). This variant has also been reported in the compound heterozygous state in an individual affected with atypical ataxia-telangiectasia (PMID: 31050087). Lymphoblastoid cell lines derived from this individual showed in-frame skipping of exon 31 (PMID: 31050087). This variant was reported in an individual affected with ovarian cancer (PMID: 34371384). This variant has been identified in 1/244648 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 24, 2024	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2020

Canonical splice site variant demonstrated to result in an in-frame deletion of exon 31 (Fivet 2019); Observed in an individual with familial breast cancer; however, the variant was not found in an affected sister (Bubien 2017); Observed with other ATM variants in unrelated patients with ataxia-telangiectasia, but it was not reported whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Broccoletti 2011, Fivet 2019); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31050087, 22763152, 28691344, 20840352) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		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: rs771117943; hg19: chr11-108164205;