11-108235839-G-A

Variant names:

• chr11-108235839-G-A
• rs796051858
• NM_000051.4:c.496+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_000051.4(ATM):​c.496+5G>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 0.00000274 in 1,461,422 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000273575: Functional analysis of cDNA from the patient's lymphoblastoid cell line by Dö" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 2.62
• Publications: 8 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000273575: Functional analysis of cDNA from the patient's lymphoblastoid cell line by Dörk T et al. revealed an in-frame deletion of coding exon 4 (described as exon 7 in the manuscript). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV000687588: "Functional studies found moderate radial sensitivity and chromosomal instability (PMID: 15054841, 19535770) and severe disruption to kinase activity (PMID: 21778326)."; SCV000293428: Published RNA studies demonstrate aberrant splicing, resulting in both in-frame and out-of-frame transcripts (PMID: 15054841, 35716007, 37438524); SCV000622549: Studies have shown that this variant results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 15054841, 35716007; internal data).; SCV004039500: This variant results in skipping of exon 5 (Dork_2004) and another suggests that this variant results in leaky splicing (Bueno-Martinez_2022).; SCV001424016: cells had markedly reduced phosphorylation activity toward p53 and NBS1/p95 after radiation exposure (PMID: 15054841).
• 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 11-108235839-G-A is Pathogenic according to our data. Variant chr11-108235839-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3047.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.496+5G>A		splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.496+5G>A		splice_region 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.496+5G>A		splice_region intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.496+5G>A		splice_region intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.496+5G>A		splice_region intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727034

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000207 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Ataxia-telangiectasia syndrome (5)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Ataxia - telangiectasia variant (1)
1	-	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.25	T
PhyloP100		2.6
Sift4G	Benign	0.089	T
Vest4		0.12
MVP		0.93
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: -5

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

Other links and lift over

dbSNP: rs796051858; hg19: chr11-108106566;