rs587781905

Variant names:

• chr11-108331441-TAGAG-T
• rs587781905
• NM_000051.4:c.7517_7520delGAGA

Your query was ambiguous. Multiple possible variants found:

• chr11-108331441-TAGAG-T
• chr11-108331441-TAGAG-TAG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):​c.7517_7520delGAGA​(p.Arg2506fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,600 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000546740: Studies have shown that this premature translational stop signal results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data).". Synonymous variant affecting the same amino acid position (i.e. R2506R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.62
• Publications: 12 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

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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000546740: Studies have shown that this premature translational stop signal results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108331441-TAGAG-T is Pathogenic according to our data. Variant chr11-108331441-TAGAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 141647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.7517_7520delGAGA	p.Arg2506fs	frameshift splice_region	Exon 51 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7517_7520delGAGA	p.Arg2506fs	frameshift splice_region	Exon 52 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-22374_641-22371delCTCT		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.7517_7520delGAGA	p.Arg2506fs	frameshift splice_region	Exon 51 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7517_7520delGAGA	p.Arg2506fs	frameshift splice_region	Exon 52 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1392_*1395delCTCT		3_prime_UTR	Exon 13 of 13	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250380 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460600 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726624

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111428

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Ataxia-telangiectasia syndrome (6)
4	-	-	not provided (4)
3	-	-	Familial cancer of breast (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	Familial colorectal cancer type X (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 7
DS_AL_spliceai		1.0		Position offset: 3

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

Other links and lift over

dbSNP: rs587781905; hg19: chr11-108202168; COSMIC: COSV108796282;