Variant rs864622543 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000051.4(ATM):c.3994-159A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 520,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATM
NM_000051.4 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -2.34

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108287441-A-G is Pathogenic according to our data. Variant chr11-108287441-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108287441-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.3994-159A>G		intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.3994-159A>G		intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000272

AC:

AN:

367878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

195278

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000428

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 09, 2023

This sequence change falls in intron 26 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with ataxia telangiectasia (PMID: 15643608; Invitae). This variant is also known as IVS28‚Äì159A>G. ClinVar contains an entry for this variant (Variation ID: 220483). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 15643608; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2024

Non-canonical splice site variant demonstrated to result in aberrant transcripts containing intronic sequences leading to loss of function (PMID: 15643608, 37438524); In silico analysis suggests this variant may impact gene splicing; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19823873, 37438524, 35145552, 17389389, 32899500, 35140743, 24506781, 15643608) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.3994-159A>G intronic variant results from an A to G substitution 159 nucleotides upstream from coding exon 26 in the ATM gene. This alteration has been reported in an individual with ataxia-telangiectasia (A-T) (Coutinho G et al. Hum. Mutat. 2005 Feb;25:118-24). RNA analyses have shown that this alteration causes aberrant splicing with the retention of intronic sequences in the mRNA (Coutinho G et al. Hum. Mutat. 2005 Feb;25:118-24; Ambry internal data). Of note, this alteration is also designated as IVS28-159A>G in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

8.0

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.35

Position offset: -24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over