rs587780634

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):c.6343G>A(p.Val2115Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000419 in 1,600,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. V2115L) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:2O:1

Conservation

PhyloP100: 4.26

Publications

8 publications found

Variant links:

COSMIC-nc: COSV106056203

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

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16438726).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	NM_000051.4	MANE Select	c.6343G>A	p.Val2115Ile	missense	Exon 43 of 63	NP_000042.3
ATM	NM_001351834.2		c.6343G>A	p.Val2115Ile	missense	Exon 44 of 64	NP_001338763.1	Q13315
C11orf65	NM_001330368.2		c.641-8446C>T		intron	N/A	NP_001317297.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.6343G>A	p.Val2115Ile	missense	Exon 43 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.6343G>A	p.Val2115Ile	missense	Exon 44 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000527805.6	TSL:1	n.*1407G>A		non_coding_transcript_exon	Exon 41 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes

AF:

0.000102

AC:

AN:

146992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000673

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:

0.0000891

Gnomad OTH

AF:

0.000491

GnomAD2 exomes

AF:

0.0000321

AC:

AN:

249350

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000358

AC:

AN:

1453832

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

723208

show subpopulations

African (AFR)

AF:

0.0000904

AC:

AN:

33182

American (AMR)

AF:

0.0000449

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25818

East Asian (EAS)

AF:

0.00

AC:

AN:

39194

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000397

AC:

AN:

1107040

Other (OTH)

AF:

0.0000167

AC:

AN:

59848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000102

AC:

AN:

146992

Hom.:

Cov.:

AF XY:

0.0000838

AC XY:

AN XY:

71598

show subpopulations

African (AFR)

AF:

0.000182

AC:

AN:

38500

American (AMR)

AF:

0.0000673

AC:

AN:

14860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5078

South Asian (SAS)

AF:

0.00

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

67376

Other (OTH)

AF:

0.000491

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000386

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000595

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia syndrome (5)

Hereditary cancer-predisposing syndrome (4)

Familial cancer of breast (3)

not provided (3)

not specified (2)

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

Breast and/or ovarian cancer (1)

Ataxia-telangiectasia syndrome;C0027672:Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.058

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.50

M_CAP

Benign

0.073

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

4.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.47

REVEL

Benign

0.21

Sift

Benign

0.39

Sift4G

Benign

0.45

Polyphen

0.67

Vest4

0.34

MVP

0.66

MPC

0.10

ClinPred

0.065

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.098

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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