11-108289623-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):c.4258C>T(p.Leu1420Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,605,174 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1420V) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 249 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27O:1

Conservation

PhyloP100: 0.809

Publications

64 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

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0078905225).

BP6

Variant 11-108289623-C-T is Benign according to our data. Variant chr11-108289623-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1720/152268) while in subpopulation NFE AF = 0.0186 (1266/67990). AF 95% confidence interval is 0.0178. There are 16 homozygotes in GnomAd4. There are 792 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR,AD 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.4258C>T	p.Leu1420Phe	missense	Exon 29 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4258C>T	p.Leu1420Phe	missense	Exon 30 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.4258C>T	p.Leu1420Phe	missense	Exon 29 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.4258C>T	p.Leu1420Phe	missense	Exon 30 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.4258C>T	p.Leu1420Phe	missense	Exon 29 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1720

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.00933

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.0110

AC:

2715

AN:

245854

AF XY:

0.0114

show subpopulations

Gnomad AFR exome

AF:

0.00291

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00154

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.00992

GnomAD4 exome

AF:

0.0167

AC:

24336

AN:

1452906

Hom.:

249

Cov.:

AF XY:

0.0165

AC XY:

11933

AN XY:

721996

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

33124

American (AMR)

AF:

0.00399

AC:

174

AN:

43636

Ashkenazi Jewish (ASJ)

AF:

0.00155

AC:

AN:

25870

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39556

South Asian (SAS)

AF:

0.00768

AC:

650

AN:

84652

European-Finnish (FIN)

AF:

0.0107

AC:

568

AN:

53182

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

4892

European-Non Finnish (NFE)

AF:

0.0199

AC:

22009

AN:

1108092

Other (OTH)

AF:

0.0132

AC:

789

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1119

2237

3356

4474

5593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.0113

AC:

1720

AN:

152268

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

792

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00346

AC:

144

AN:

41570

American (AMR)

AF:

0.00621

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00891

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00933

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0186

AC:

1266

AN:

67990

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

165

248

330

413

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:

0.0159

Hom.:

102

Bravo

AF:

0.0108

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00364

AC:

ESP6500EA

AF:

0.0178

AC:

153

ExAC

AF:

0.0120

AC:

1461

Asia WGS

AF:

0.00202

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (13)

Hereditary cancer-predisposing syndrome (5)

Ataxia-telangiectasia syndrome (4)

not provided (2)

Breast and/or ovarian cancer (1)

Familial cancer of breast (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.2

PhyloP100

0.81

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.15

Sift

Benign

0.071

Sift4G

Benign

0.061

Polyphen

0.15

Vest4

0.22

MPC

0.17

ClinPred

0.020

GERP RS

-0.47

Varity_R

0.089

gMVP

0.53

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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