rs4986839

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):c.8786+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,604,136 control chromosomes in the GnomAD database, including 1,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 57 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1143 hom. )

Consequence

ATM
NM_000051.4 splice_region, intron

Scores

Splicing: ADA: 0.00002930

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27

Conservation

PhyloP100: 0.222

Variant links:

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 links:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 11-108353888-A-C is Benign according to our data. Variant chr11-108353888-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 132696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108353888-A-C is described in Lovd as [Benign]. Variant chr11-108353888-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0246 (3740/152182) while in subpopulation NFE AF= 0.0377 (2565/68000). AF 95% confidence interval is 0.0365. There are 57 homozygotes in gnomad4. There are 1715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 57 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8786+8A>C		splice_region_variant, intron_variant	Intron 60 of 62	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8786+8A>C		splice_region_variant, intron_variant	Intron 60 of 62		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3742

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00776

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0212

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.00792

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0377

Gnomad OTH

AF:

0.0315

GnomAD3 exomes

AF:

0.0262

AC:

6577

AN:

251450

Hom.:

154

AF XY:

0.0267

AC XY:

3635

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.0173

Gnomad ASJ exome

AF:

0.0829

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0153

Gnomad FIN exome

AF:

0.00845

Gnomad NFE exome

AF:

0.0368

Gnomad OTH exome

AF:

0.0329

GnomAD4 exome

AF:

0.0356

AC:

51622

AN:

1451954

Hom.:

1143

Cov.:

AF XY:

0.0348

AC XY:

25143

AN XY:

723064

show subpopulations

Gnomad4 AFR exome

AF:

0.00635

Gnomad4 AMR exome

AF:

0.0179

Gnomad4 ASJ exome

AF:

0.0829

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0161

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.0402

Gnomad4 OTH exome

AF:

0.0332

GnomAD4 genome

AF:

0.0246

AC:

3740

AN:

152182

Hom.:

Cov.:

AF XY:

0.0230

AC XY:

1715

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00773

Gnomad4 AMR

AF:

0.0211

Gnomad4 ASJ

AF:

0.0795

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.00792

Gnomad4 NFE

AF:

0.0377

Gnomad4 OTH

AF:

0.0307

Alfa

AF:

0.0375

Hom.:

Bravo

AF:

0.0261

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome

Benign:6

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:6

May 11, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 04, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2012

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: 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. -

not provided

Benign:5

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.8786+8A>C variant was identified in 12 of 206 proband chromosomes (frequency: 0.06) from individuals or families with acute lymphoblastic leukemia and was present in 3 of 198 control chromosomes (frequency: 0.02) from healthy individuals (Meier 2005). The variant was also identified in dbSNP (ID: rs4986839) as "With Likely benign, other allele", ClinVar (classified as benign by seven submitters and as likely benign by four submitters) and LOVD 3.0 (4x as benign or likely benign). The variant was identified in control databases in 7055 of 277176 chromosomes (163 homozygous) at a frequency of 0.03, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 165 of 24026 chromosomes (freq: 0.007), Other in 208 of 6464 chromosomes (freq: 0.03), Latino in 582 of 34416 chromosomes (freq: 0.02), European in 4586 of 126678 chromosomes (freq: 0.04), Ashkenazi Jewish in 836 of 10150 chromosomes (freq: 0.08), Finnish in 216 of 25792 chromosomes (freq: 0.008), and South Asian in 462 of 30782 chromosomes (freq: 0.02), while the variant was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.8

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over