rs149096247

Variant names:

• chr11-108271230-T-G
• rs149096247
• NM_000051.4:c.2922-21T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.2922-21T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 629,316 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (0 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.137
• Publications: 1 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):

• 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, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-108271230-T-G is Benign according to our data. Variant chr11-108271230-T-G is described in ClinVar as Benign. ClinVar VariationId is 136438.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 = 0.00787 (1147/145742) while in subpopulation AFR AF = 0.0253 (1018/40168). AF 95% confidence interval is 0.0241. There are 8 homozygotes in GnomAd4. There are 540 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.2922-21T>G		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.2922-21T>G		intron	N/A	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.2922-21T>G		intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.2922-21T>G		intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.2922-21T>G		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1145 AN: 145706 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000440

Gnomad OTH AF: 0.00853

GnomAD2 exomes AF: 0.00468 AC: 635 AN: 135742 AF XY: 0.00372

Gnomad AFR exome AF: 0.0461

Gnomad AMR exome AF: 0.00823

Gnomad ASJ exome AF: 0.00243

Gnomad EAS exome AF: 0.0000906

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.00320 AC: 1549 AN: 483574 Hom.: 0 Cov.: 31 AF XY: 0.00292 AC XY: 735 AN XY: 251724

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

African (AFR) AF: 0.0566 AC: 704 AN: 12442

American (AMR) AF: 0.00843 AC: 185 AN: 21952

Ashkenazi Jewish (ASJ) AF: 0.00550 AC: 55 AN: 9994

East Asian (EAS) AF: 0.00 AC: 0 AN: 14624

South Asian (SAS) AF: 0.000132 AC: 6 AN: 45570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23108

Middle Eastern (MID) AF: 0.0135 AC: 39 AN: 2898

European-Non Finnish (NFE) AF: 0.00108 AC: 358 AN: 332362

Other (OTH) AF: 0.00979 AC: 202 AN: 20624

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00787 AC: 1147 AN: 145742 Hom.: 8 Cov.: 32 AF XY: 0.00762 AC XY: 540 AN XY: 70838

African (AFR) AF: 0.0253 AC: 1018 AN: 40168

American (AMR) AF: 0.00504 AC: 74 AN: 14688

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 7 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.000425 AC: 2 AN: 4702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000440 AC: 29 AN: 65836

Other (OTH) AF: 0.00847 AC: 17 AN: 2006

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00839

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.6
DANN	Benign	0.22
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149096247;

hg19: chr11-108141957;