11-108250683-CTTTTTTT-CTTTTTTTTTT

Variant names:

• chr11-108250683-C-CTTT
• rs34325032
• NM_000051.4:c.1236-5_1236-3dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000051.4(ATM):​c.1236-5_1236-3dupTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.510
• Publications: 10 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040562645 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGgct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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.1236-5_1236-3dupTTT		splice_acceptor intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.1236-5_1236-3dupTTT		splice_acceptor 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.1236-18_1236-17insTTT		intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.1236-18_1236-17insTTT		intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.1236-18_1236-17insTTT		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 142258 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000636 AC: 104 AN: 163404 AF XY: 0.000730

Gnomad AFR exome AF: 0.000283

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.000286

Gnomad EAS exome AF: 0.000619

Gnomad FIN exome AF: 0.000674

Gnomad NFE exome AF: 0.000524

Gnomad OTH exome AF: 0.000484

GnomAD4 exome AF: 0.000142 AC: 193 AN: 1362640 Hom.: 0 Cov.: 0 AF XY: 0.000140 AC XY: 95 AN XY: 678966

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

African (AFR) AF: 0.000162 AC: 5 AN: 30926

American (AMR) AF: 0.000821 AC: 32 AN: 38974

Ashkenazi Jewish (ASJ) AF: 0.000164 AC: 4 AN: 24434

East Asian (EAS) AF: 0.0000782 AC: 3 AN: 38350

South Asian (SAS) AF: 0.000430 AC: 34 AN: 79044

European-Finnish (FIN) AF: 0.000155 AC: 6 AN: 38602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4656

European-Non Finnish (NFE) AF: 0.0000990 AC: 104 AN: 1050956

Other (OTH) AF: 0.0000882 AC: 5 AN: 56698

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 142258 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68524

African (AFR) AF: 0.00 AC: 0 AN: 38538

American (AMR) AF: 0.00 AC: 0 AN: 14256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 4906

South Asian (SAS) AF: 0.00 AC: 0 AN: 4530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65522

Other (OTH) AF: 0.00 AC: 0 AN: 1946

Alfa AF: 0.000429 Hom.: 575

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.51

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34325032; hg19: chr11-108121410;