11-108253759-T-G

Position:

• chr11-108253759-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.1899-55T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,348,084 control chromosomes in the GnomAD database, including 1,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (105 hom., cov: 32)
  • Exomes 𝑓: 0.039 (999 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.845

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-108253759-T-G is Benign according to our data. Variant chr11-108253759-T-G is described in ClinVar as [Benign]. Clinvar id is 453393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108253759-T-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.1899-55T>G		intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1899-55T>G		intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4608 AN: 152166 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.00675

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0379

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0464

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.0388 AC: 46347 AN: 1195800 Hom.: 999 AF XY: 0.0388 AC XY: 23601 AN XY: 607608

Gnomad4 AFR exome AF: 0.00632

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0524

Gnomad4 EAS exome AF: 0.000131

Gnomad4 SAS exome AF: 0.0299

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0426

Gnomad4 OTH exome AF: 0.0391

GnomAD4 genome AF: 0.0303 AC: 4607 AN: 152284 Hom.: 105 Cov.: 32 AF XY: 0.0302 AC XY: 2249 AN XY: 74466

Gnomad4 AFR AF: 0.00673

Gnomad4 AMR AF: 0.0238

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0379

Gnomad4 NFE AF: 0.0464

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0333 Hom.: 39

Bravo AF: 0.0273

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 27599564) -

Ataxia-telangiectasia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.62
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4987951; hg19: chr11-108124486;