chr11-108272455-C-T

Variant names:

• chr11-108272455-C-T
• rs664677
• NM_000051.4:c.3078-77C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.3078-77C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,221,380 control chromosomes in the GnomAD database, including 216,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32574 hom., cov: 32)
  • Exomes 𝑓: 0.58 (184251 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.433
• Publications: 70 publications found

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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-108272455-C-T is Benign according to our data. Variant chr11-108272455-C-T is described in ClinVar as Benign. ClinVar VariationId is 439418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.3078-77C>T		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.3078-77C>T		intron	N/A	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.3078-77C>T		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.3078-77C>T		intron	N/A	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.3078-77C>T		intron	N/A	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98265 AN: 151956 Hom.: 32524 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.584 AC: 623986 AN: 1069306 Hom.: 184251 AF XY: 0.586 AC XY: 321831 AN XY: 548864

African (AFR) AF: 0.783 AC: 19881 AN: 25378

American (AMR) AF: 0.656 AC: 27968 AN: 42626

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 15218 AN: 23496

East Asian (EAS) AF: 0.403 AC: 15149 AN: 37598

South Asian (SAS) AF: 0.646 AC: 49587 AN: 76806

European-Finnish (FIN) AF: 0.627 AC: 33061 AN: 52704

Middle Eastern (MID) AF: 0.757 AC: 3067 AN: 4054

European-Non Finnish (NFE) AF: 0.568 AC: 431747 AN: 759522

Other (OTH) AF: 0.601 AC: 28308 AN: 47122

GnomAD4 genome AF: 0.647 AC: 98366 AN: 152074 Hom.: 32574 Cov.: 32 AF XY: 0.650 AC XY: 48325 AN XY: 74298

African (AFR) AF: 0.783 AC: 32473 AN: 41492

American (AMR) AF: 0.672 AC: 10260 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2337 AN: 3470

East Asian (EAS) AF: 0.397 AC: 2043 AN: 5152

South Asian (SAS) AF: 0.653 AC: 3152 AN: 4824

European-Finnish (FIN) AF: 0.632 AC: 6670 AN: 10562

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39244 AN: 67996

Other (OTH) AF: 0.654 AC: 1378 AN: 2108

Alfa AF: 0.586 Hom.: 8428

Bravo AF: 0.653

Asia WGS AF: 0.590 AC: 2049 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 12, 2023

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 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Ataxia-telangiectasia syndrome Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.26
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs664677; hg19: chr11-108143182; COSMIC: COSV53773448; COSMIC: COSV53773448;