11-108317366-T-A

Variant names:

• chr11-108317366-T-A
• rs1060501631
• NM_000051.4:c.6199-7T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 PP3_Strong PP5

The NM_000051.4(ATM):​c.6199-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005901838: An internal RNA assay with primers annealing exons 41 and 45, in cultured lymphocytes from a carrier patient in the presence of NMD-inhibition was performed. Two aberrant transcripts were observed, a partial intron 42 retention of the last 5 intronic bp (r.6198_6199ins6199-5_6199-1), which is predicted to lead to a truncated protein (p.Ala2067Phefs*17), and also a partial skipping of 49 bp at the 5’ end of exon 43 (r.6199_6247del), also generating a translational frameshift (p.Ala2067Aspfs*13). These results are in line with the splicing predictions. None of these transcripts was detected in controls (unpublished data).". The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 1.26
• 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

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005901838: An internal RNA assay with primers annealing exons 41 and 45, in cultured lymphocytes from a carrier patient in the presence of NMD-inhibition was performed. Two aberrant transcripts were observed, a partial intron 42 retention of the last 5 intronic bp (r.6198_6199ins6199-5_6199-1), which is predicted to lead to a truncated protein (p.Ala2067Phefs*17), and also a partial skipping of 49 bp at the 5’ end of exon 43 (r.6199_6247del), also generating a translational frameshift (p.Ala2067Aspfs*13). These results are in line with the splicing predictions. None of these transcripts was detected in controls (unpublished data).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108317366-T-A is Pathogenic according to our data. Variant chr11-108317366-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407606.

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.6199-7T>A		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.6199-7T>A		splice_region intron	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-8295A>T		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.6199-7T>A		splice_region intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6199-7T>A		splice_region intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1263-7T>A		splice_region intron	N/A	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458046 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725464

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109516

Other (OTH) AF: 0.0000166 AC: 1 AN: 60094

GnomAD4 genome Cov.: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Ataxia-telangiectasia syndrome (2)
1	1	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.82
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.61		Position offset: 2
DS_AL_spliceai		0.49		Position offset: 7

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

Other links and lift over

dbSNP: rs1060501631; hg19: chr11-108188093;