rs587781368

chr11-108280980-T-TAchr11-108280980-T-TAAchr11-108280980-TA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000051.4(ATM):c.3403-13dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,555,222 control chromosomes in the GnomAD database, including 239,756 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23487 hom., cov: 0)
  • Exomes 𝑓: 0.56 (216269 hom.)
• Consequence: ATM NM_000051.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.133

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 11-108280980-T-TA is Benign according to our data. Variant chr11-108280980-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 181858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3403-13dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3403-13dup		splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83626 AN: 151636 Hom.: 23475 Cov.: 0

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.582

GnomAD3 exomes AF: 0.560 AC: 129971 AN: 231976 Hom.: 36500 AF XY: 0.565 AC XY: 71112 AN XY: 125826

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.611

Gnomad EAS exome AF: 0.379

Gnomad SAS exome AF: 0.614

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.557 AC: 782075 AN: 1403468 Hom.: 216269 Cov.: 31 AF XY: 0.561 AC XY: 392636 AN XY: 699554

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.612

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.624

Gnomad4 FIN exome AF: 0.615

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.551 AC: 83667 AN: 151754 Hom.: 23487 Cov.: 0 AF XY: 0.558 AC XY: 41377 AN XY: 74200

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.628

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.583

Alfa AF: 0.539 Hom.: 3337

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2014	The variant is found in HEREDICANCER,BR-OV-HEREDIC,COLO-HEREDIC panel(s). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2012	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 26, 2015	- -

Ataxia-telangiectasia syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3218681; hg19: chr11-108151707;