rs3092829

Variant names:

• chr11-108304667-T-C
• rs3092829
• NM_000051.4:c.5497-8T>C

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.5497-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,612,812 control chromosomes in the GnomAD database, including 710 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (36 hom., cov: 32)
  • Exomes 𝑓: 0.028 (674 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006728
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.28
• Publications: 23 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-108304667-T-C is Benign according to our data. Variant chr11-108304667-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3271/152312) while in subpopulation NFE AF = 0.0329 (2238/68020). AF 95% confidence interval is 0.0318. There are 36 homozygotes in GnomAd4. There are 1549 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.5497-8T>C		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.5497-8T>C		splice_region 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.5497-8T>C		splice_region intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.5497-8T>C		splice_region intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*561-8T>C		splice_region intron	N/A	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3272 AN: 152194 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0225 AC: 5630 AN: 250650 AF XY: 0.0226

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0283 AC: 41334 AN: 1460500 Hom.: 674 Cov.: 31 AF XY: 0.0280 AC XY: 20345 AN XY: 726626

African (AFR) AF: 0.00490 AC: 164 AN: 33450

American (AMR) AF: 0.0198 AC: 886 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 657 AN: 26124

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39660

South Asian (SAS) AF: 0.00624 AC: 538 AN: 86220

European-Finnish (FIN) AF: 0.0265 AC: 1415 AN: 53314

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5762

European-Non Finnish (NFE) AF: 0.0324 AC: 35957 AN: 1110930

Other (OTH) AF: 0.0261 AC: 1577 AN: 60344

GnomAD4 genome AF: 0.0215 AC: 3271 AN: 152312 Hom.: 36 Cov.: 32 AF XY: 0.0208 AC XY: 1549 AN XY: 74486

African (AFR) AF: 0.00524 AC: 218 AN: 41570

American (AMR) AF: 0.0232 AC: 355 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0329 AC: 2238 AN: 68020

Other (OTH) AF: 0.0284 AC: 60 AN: 2110

Alfa AF: 0.0303 Hom.: 79

Bravo AF: 0.0214

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0329

EpiControl AF: 0.0321

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	Ataxia-telangiectasia syndrome (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	2	Familial cancer of breast (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Triple-negative breast carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Benign	0.82
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.0040
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: rs3092829; hg19: chr11-108175394; COSMIC: COSV53727999;