11-108304736-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000051.4(ATM):c.5558A>T(p.Asp1853Val) variant causes a missense change. The variant allele was found at a frequency of 0.00484 in 1,614,054 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1853N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 27 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:33O:1

Conservation

PhyloP100: 5.47

Publications

75 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016077608).

BP6

Variant 11-108304736-A-T is Benign according to our data. Variant chr11-108304736-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133623.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00439 (668/152296) while in subpopulation NFE AF = 0.00729 (496/68028). AF 95% confidence interval is 0.00676. There are 0 homozygotes in GnomAd4. There are 311 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 27 AD,AR gene

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.5558A>T	p.Asp1853Val	missense	Exon 37 of 63	NP_000042.3
	ATM	NM_001351834.2		c.5558A>T	p.Asp1853Val	missense	Exon 38 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.5558A>T	p.Asp1853Val	missense	Exon 37 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.5558A>T	p.Asp1853Val	missense	Exon 38 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000527805.6	TSL:1	n.*622A>T		non_coding_transcript_exon	Exon 35 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes

AF:

0.00439

AC:

668

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00729

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00488

AC:

1226

AN:

250992

AF XY:

0.00522

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00662

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00489

AC:

7150

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

3592

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33472

American (AMR)

AF:

0.00315

AC:

141

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.00579

AC:

499

AN:

86252

European-Finnish (FIN)

AF:

0.00360

AC:

192

AN:

53402

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00521

AC:

5789

AN:

1111950

Other (OTH)

AF:

0.00502

AC:

303

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

398

795

1193

1590

1988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.00439

AC:

668

AN:

152296

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

311

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41544

American (AMR)

AF:

0.00294

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00497

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00729

AC:

496

AN:

68028

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00653

Hom.:

Bravo

AF:

0.00389

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00516

AC:

627

Asia WGS

AF:

0.00231

AC:

AN:

3476

EpiCase

AF:

0.00698

EpiControl

AF:

0.00670

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia syndrome (8)

not provided (7)

not specified (8)

Hereditary cancer-predisposing syndrome (6)

Familial cancer of breast (2)

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)

Breast and/or ovarian cancer (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.016

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.5

PhyloP100

5.5

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.59

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Polyphen

0.88

Vest4

0.67

MVP

0.86

MPC

0.23

ClinPred

0.032

GERP RS

5.5

Varity_R

0.61

gMVP

0.58

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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