NM_000051.4:c.4768C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP3BP6

The NM_000051.4(ATM):c.4768C>T(p.Leu1590Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000127 in 1,610,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. L1590R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:6

Conservation

PhyloP100: 5.11

Publications

14 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 30 uncertain in NM_000051.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

BP6

Variant 11-108293469-C-T is Benign according to our data. Variant chr11-108293469-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181961.

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.4768C>T	p.Leu1590Phe	missense	Exon 31 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4768C>T	p.Leu1590Phe	missense	Exon 32 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.4768C>T	p.Leu1590Phe	missense	Exon 31 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.4768C>T	p.Leu1590Phe	missense	Exon 32 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.4437-1458C>T		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000128

AC:

AN:

250352

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1458396

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

725732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39516

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.000146

AC:

162

AN:

1109516

Other (OTH)

AF:

0.000116

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000178

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

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:

0.000310

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (4)

not provided (4)

Ataxia-telangiectasia syndrome (3)

Familial cancer of breast (3)

not specified (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.029

MutationAssessor

Uncertain

2.6

PhyloP100

5.1

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.85

MVP

0.95

MPC

0.61

ClinPred

0.88

GERP RS

5.3

Varity_R

0.47

gMVP

0.54

Mutation Taster

=25/75

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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