ENST00000533733.6:n.2423A>G

Variant names:

• chr11-108290525-A-G
• rs647681
• ENST00000533733.6:n.2423A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000533733.6(ATM):​n.2423A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 152,958 control chromosomes in the GnomAD database, including 29,755 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29402 hom., cov: 27)
  • Exomes 𝑓: 0.59 (353 hom.)
• Consequence: ATM ENST00000533733.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.966
• Publications: 5 publications found

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):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.4436+724A>G		intron_variant	Intron 29 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4436+724A>G		intron_variant	Intron 29 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 93645 AN: 150904 Hom.: 29372 Cov.: 27

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.586 AC: 1135 AN: 1936 Hom.: 353 Cov.: 0 AF XY: 0.591 AC XY: 882 AN XY: 1492

African (AFR) AF: 0.765 AC: 26 AN: 34

American (AMR) AF: 0.607 AC: 17 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 8 AN: 14

East Asian (EAS) AF: 0.446 AC: 50 AN: 112

South Asian (SAS) AF: 0.500 AC: 17 AN: 34

European-Finnish (FIN) AF: 0.438 AC: 7 AN: 16

Middle Eastern (MID) AF: 0.786 AC: 11 AN: 14

European-Non Finnish (NFE) AF: 0.596 AC: 958 AN: 1608

Other (OTH) AF: 0.539 AC: 41 AN: 76

GnomAD4 genome AF: 0.621 AC: 93721 AN: 151022 Hom.: 29402 Cov.: 27 AF XY: 0.625 AC XY: 46048 AN XY: 73722

African (AFR) AF: 0.692 AC: 28461 AN: 41152

American (AMR) AF: 0.660 AC: 10000 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2324 AN: 3466

East Asian (EAS) AF: 0.396 AC: 2011 AN: 5072

South Asian (SAS) AF: 0.654 AC: 3120 AN: 4770

European-Finnish (FIN) AF: 0.633 AC: 6555 AN: 10358

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39114 AN: 67754

Other (OTH) AF: 0.633 AC: 1326 AN: 2096

Alfa AF: 0.496 Hom.: 1544

Bravo AF: 0.622

Asia WGS AF: 0.581 AC: 2019 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs647681; hg19: chr11-108161252;