Genetic Variant ATM:c.6572+12G>T (chr11-108321432-G-T) – ACMG Classification: Benign (-20 pts)

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.6572+12G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,613,882 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 36 hom. )

Consequence

ATM
NM_000051.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -0.280

Publications

5 publications found

Variant links:

COSMIC-nc: COSV53733563

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

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 11-108321432-G-T is Benign according to our data. Variant chr11-108321432-G-T is described in ClinVar as Benign. ClinVar VariationId is 140762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1874/152194) while in subpopulation AFR AF = 0.042 (1742/41494). AF 95% confidence interval is 0.0403. There are 48 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATM	NM_000051.4	MANE Select	c.6572+12G>T	intron	N/A	NP_000042.3
ATM	NM_001351834.2		c.6572+12G>T	intron	N/A	NP_001338763.1	Q13315
C11orf65	NM_001330368.2		c.641-12361C>A	intron	N/A	NP_001317297.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.6572+12G>T	intron	N/A	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.6572+12G>T	intron	N/A	ENSP00000388058.2	Q13315
ATM	ENST00000527805.6	TSL:1	n.*1636+12G>T	intron	N/A	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1867

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00636

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00339

AC:

852

AN:

251426

AF XY:

0.00240

show subpopulations

Gnomad AFR exome

AF:

0.0458

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00128

AC:

1874

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

830

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0432

AC:

1446

AN:

33476

American (AMR)

AF:

0.00268

AC:

120

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000105

AC:

117

AN:

1111886

Other (OTH)

AF:

0.00280

AC:

169

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0123

AC:

1874

AN:

152194

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0420

AC:

1742

AN:

41494

American (AMR)

AF:

0.00635

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68016

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

186

278

371

464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000737

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Ataxia-telangiectasia syndrome (3)

Hereditary cancer-predisposing syndrome (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

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.060

(source)

DANN

Benign

0.62

PhyloP100

-0.28

Mutation Taster

=100/0

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

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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