NM_000051.4:c.-30-989A>G

Variant names:

• chr11-108226606-A-G
• rs228591
• NM_000051.4:c.-30-989A>G

Variant summary

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

The NM_000051.4(ATM):​c.-30-989A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 152,094 control chromosomes in the GnomAD database, including 22,673 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 0.54 (22672 hom., cov: 32)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.362
• Publications: 26 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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.-30-989A>G		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.-30-989A>G		intron	N/A	NP_001338763.1
	ATM	NM_001351835.2		c.-30-989A>G		intron	N/A	NP_001338764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.-30-989A>G		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.-30-989A>G		intron	N/A	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.-30-989A>G		intron	N/A	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81989 AN: 151964 Hom.: 22659 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.569

GnomAD4 exome AF: 0.500 AC: 6 AN: 12 Hom.: 1 Cov.: 0 AF XY: 0.400 AC XY: 4 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00921106), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.539 AC: 82030 AN: 152082 Hom.: 22672 Cov.: 32 AF XY: 0.547 AC XY: 40664 AN XY: 74344

African (AFR) AF: 0.424 AC: 17598 AN: 41478

American (AMR) AF: 0.624 AC: 9541 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2222 AN: 3468

East Asian (EAS) AF: 0.433 AC: 2248 AN: 5186

South Asian (SAS) AF: 0.648 AC: 3125 AN: 4822

European-Finnish (FIN) AF: 0.629 AC: 6656 AN: 10576

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38633 AN: 67946

Other (OTH) AF: 0.570 AC: 1201 AN: 2108

Alfa AF: 0.563 Hom.: 73880

Bravo AF: 0.531

Asia WGS AF: 0.571 AC: 1986 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.8
DANN	Benign	0.67
PhyloP100		-0.36
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: rs228591; hg19: chr11-108097333;