11-108329209-CCTTAGG-C

Variant names:

• chr11-108329209-CCTTAGG-C
• rs796051856
• NM_000051.4:c.7279_7284delCTTAGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000051.4(ATM):​c.7279_7284delCTTAGG​(p.Leu2427_Arg2428del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L2427L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 48 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000051.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-108329209-CCTTAGG-C is Pathogenic according to our data. Variant chr11-108329209-CCTTAGG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3020.Status of the report is no_assertion_criteria_provided, 0 stars.

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.7279_7284delCTTAGG	p.Leu2427_Arg2428del	conservative_inframe_deletion	Exon 49 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7279_7284delCTTAGG	p.Leu2427_Arg2428del	conservative_inframe_deletion	Exon 50 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-20144_641-20139delCCTAAG		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.7279_7284delCTTAGG	p.Leu2427_Arg2428del	conservative_inframe_deletion	Exon 49 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.7279_7284delCTTAGG	p.Leu2427_Arg2428del	conservative_inframe_deletion	Exon 50 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*2343_*2348delCTTAGG		non_coding_transcript_exon	Exon 47 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Jun 23, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs796051856; hg19: chr11-108199936;