rs1799757

Positions:

• chr11-108279480-CT-C
• chr11-108279480-CT-CTT

Variant summary

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

The NM_000051.4(ATM):​c.3285-9del 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 0.129 in 1,573,082 control chromosomes in the GnomAD database, including 14,912 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1202 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13710 hom.)
• Consequence: ATM NM_000051.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.508

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 11-108279480-CT-C is Benign according to our data. Variant chr11-108279480-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 181857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108279480-CT-C is described in Lovd as [Benign]. Variant chr11-108279480-CT-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.3285-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3285-9del		splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16172 AN: 152030 Hom.: 1202 Cov.: 31

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.0918

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.00788

Gnomad SAS AF: 0.0753

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.113 AC: 25710 AN: 227570 Hom.: 1853 AF XY: 0.115 AC XY: 14159 AN XY: 122668

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.0614

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.00632

Gnomad SAS exome AF: 0.0768

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.132 AC: 187000 AN: 1420934 Hom.: 13710 Cov.: 21 AF XY: 0.131 AC XY: 92695 AN XY: 707534

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0646

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.00314

Gnomad4 SAS exome AF: 0.0772

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.106 AC: 16175 AN: 152148 Hom.: 1202 Cov.: 31 AF XY: 0.108 AC XY: 8065 AN XY: 74370

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.0916

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.00790

Gnomad4 SAS AF: 0.0762

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.103

Alfa AF: 0.125 Hom.: 256

Bravo AF: 0.0928

Asia WGS AF: 0.0370 AC: 128 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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	-	- -

Ataxia-telangiectasia syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 12, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 14, 2024

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1799757; hg19: chr11-108150207;