11-108271228-CTTTTT-CTTTTTT

Variant names:

• chr11-108271228-C-CT
• rs373881770
• NM_000051.4:c.2922-8dupT

Variant summary

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

The NM_000051.4(ATM):​c.2922-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,516,430 control chromosomes in the GnomAD database, including 197 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (196 hom., cov: 31)
  • Exomes 𝑓: 0.030 (1 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.137

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 11-108271228-C-CT is Benign according to our data. Variant chr11-108271228-C-CT is described in ClinVar as [Benign]. Clinvar id is 1249532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2922-8dupT		splice_region_variant, intron_variant	Intron 19 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2922-23_2922-22insT		intron_variant	Intron 19 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5148 AN: 142408 Hom.: 196 Cov.: 31

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.00574

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.00225

Gnomad FIN AF: 0.00634

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.0371

GnomAD4 exome AF: 0.0302 AC: 41443 AN: 1373970 Hom.: 1 Cov.: 0 AF XY: 0.0280 AC XY: 19204 AN XY: 685824

Gnomad4 AFR exome AF: 0.0694

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0171

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0362 AC: 5156 AN: 142460 Hom.: 196 Cov.: 31 AF XY: 0.0368 AC XY: 2544 AN XY: 69172

Gnomad4 AFR AF: 0.0655

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.00574

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.00226

Gnomad4 FIN AF: 0.00634

Gnomad4 NFE AF: 0.00952

Gnomad4 OTH AF: 0.0368

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Dec 20, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.2922-8dupT alters a nucleotide located close to a canonical splice site. The variant allele was found at a frequency of 0.047 in 186328 control chromosomes, predominantly at a frequency of 0.17 within the Latino subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 43.007 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Aug 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs373881770; hg19: chr11-108141955;