rs1555152058

Variant names:

• chr11-108365479-CTT-C
• rs1555152058
• NM_000051.4:c.9145_9146delTT

Your query was ambiguous. Multiple possible variants found:

• chr11-108365479-CTT-C
• chr11-108365479-CTT-CT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2_Supporting PM4 PM3

This summary comes from the ClinGen Evidence Repository: The c.9145_9146del variant in ATM is predicted to cause a change in the length of the protein (p.Phe3049Profs*13) due to a frameshift of 8 amino acids and an extension of an additional 4 amino acids. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID:10817650). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM4, PM3, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658797748/MONDO:0700270/020

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 7.64
• Publications: 0 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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.

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.9145_9146delTT	p.Phe3049ProfsTer13	frameshift	Exon 63 of 63	NP_000042.3
	ATM	NM_001351834.2		c.9145_9146delTT	p.Phe3049ProfsTer13	frameshift	Exon 64 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.640+20439_640+20440delAA		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.9145_9146delTT	p.Phe3049ProfsTer13	frameshift	Exon 63 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.9145_9146delTT	p.Phe3049ProfsTer13	frameshift	Exon 64 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*4209_*4210delTT		non_coding_transcript_exon	Exon 61 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Familial cancer of breast (2)
1	1	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Ataxia-telangiectasia syndrome (1)
-	1	-	ATM-related cancer predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 23

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

Other links and lift over

dbSNP: rs1555152058; hg19: chr11-108236206;