11-108354756-C-T

Position:

• chr11-108354756-C-T

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.8787-55C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,417,564 control chromosomes in the GnomAD database, including 227,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22541 hom., cov: 33)
  • Exomes 𝑓: 0.57 (204477 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.70

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-108354756-C-T is Benign according to our data. Variant chr11-108354756-C-T is described in ClinVar as [Benign]. Clinvar id is 1177616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108354756-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8787-55C>T		intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8787-55C>T		intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81656 AN: 151924 Hom.: 22528 Cov.: 33

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.568

GnomAD4 exome AF: 0.566 AC: 716048 AN: 1265522 Hom.: 204477 AF XY: 0.570 AC XY: 365143 AN XY: 640216

Gnomad4 AFR exome AF: 0.412

Gnomad4 AMR exome AF: 0.636

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.459

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.626

Gnomad4 NFE exome AF: 0.559

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.537 AC: 81697 AN: 152042 Hom.: 22541 Cov.: 33 AF XY: 0.545 AC XY: 40516 AN XY: 74350

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.436

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.569

Gnomad4 OTH AF: 0.569

Alfa AF: 0.413 Hom.: 1109

Bravo AF: 0.529

Asia WGS AF: 0.572 AC: 1990 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -
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 Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Ataxia-telangiectasia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.13
DANN	Benign	0.65

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: rs664982; hg19: chr11-108225483; COSMIC: COSV53733871;