11-108249043-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP2_StrongBA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The ATM c.1176C>G (p.Gly392=) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.878% (AFR) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). This is a synonymous variant (BP7) and in silico predictors find that this variant is unlikely to affect splicing (Splice AI/MaxENTScan 0%) (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA167509/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.014 ( 50 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 45 hom. )

Consequence

ATM
NM_000051.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:23

Conservation

PhyloP100: 0.835

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

ATM-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.1176C>G	p.Gly392Gly	synonymous	Exon 9 of 63	NP_000042.3
	ATM	NM_001351834.2		c.1176C>G	p.Gly392Gly	synonymous	Exon 10 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.1176C>G	p.Gly392Gly	synonymous	Exon 9 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.1176C>G	p.Gly392Gly	synonymous	Exon 10 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.1176C>G	p.Gly392Gly	synonymous	Exon 9 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2140

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00388

AC:

976

AN:

251270

AF XY:

0.00270

show subpopulations

Gnomad AFR exome

AF:

0.0517

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00150

AC:

2191

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

945

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0493

AC:

1650

AN:

33470

American (AMR)

AF:

0.00347

AC:

155

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000114

AC:

127

AN:

1111962

Other (OTH)

AF:

0.00376

AC:

227

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0141

AC:

2142

AN:

152184

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1004

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0483

AC:

2006

AN:

41522

American (AMR)

AF:

0.00641

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68006

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

100

201

301

402

502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000719

Hom.:

Bravo

AF:

0.0158

Asia WGS

AF:

0.00318

AC:

AN:

3476

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Ataxia-telangiectasia syndrome (4)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Familial cancer of breast (2)

ATM-related cancer predisposition (1)

Bile duct cancer (1)

Breast and/or ovarian cancer (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.6

(source)

DANN

Benign

0.74

PhyloP100

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over