rs146382972

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000051.4(ATM):c.334G>A(p.Ala112Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000146 in 1,604,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. A112V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:10

Conservation

PhyloP100: 5.35

Publications

11 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016045034).

BP6

Variant 11-108235672-G-A is Benign according to our data. Variant chr11-108235672-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127370.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000722 (110/152254) while in subpopulation AFR AF = 0.00248 (103/41552). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.334G>A	p.Ala112Thr	missense splice_region	Exon 5 of 63	NP_000042.3
	ATM	NM_001351834.2		c.334G>A	p.Ala112Thr	missense splice_region	Exon 6 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.334G>A	p.Ala112Thr	missense splice_region	Exon 5 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.334G>A	p.Ala112Thr	missense splice_region	Exon 6 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.334G>A	p.Ala112Thr	missense splice_region	Exon 5 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.000730

AC:

111

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000208

AC:

AN:

250218

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000861

AC:

125

AN:

1452478

Hom.:

Cov.:

AF XY:

0.0000678

AC XY:

AN XY:

723078

show subpopulations

African (AFR)

AF:

0.00280

AC:

AN:

33170

American (AMR)

AF:

0.000246

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.0000466

AC:

AN:

85920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53160

Middle Eastern (MID)

AF:

0.000374

AC:

AN:

5354

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104540

Other (OTH)

AF:

0.000216

AC:

AN:

60092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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:

0.000722

AC:

110

AN:

152254

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41552

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.000245

Hom.:

Bravo

AF:

0.000865

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Ataxia-telangiectasia syndrome (2)

not specified (2)

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

ATM-related disorder (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

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.069

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.9

PhyloP100

5.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Uncertain

0.011

Sift4G

Uncertain

0.019

Polyphen

0.87

Vest4

0.13

MVP

0.91

MPC

0.27

ClinPred

0.033

GERP RS

4.7

Varity_R

0.21

gMVP

0.39

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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