chr11-108315911-G-A

Variant names:

• chr11-108315911-G-A
• rs139770721
• NM_000051.4:c.6095G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.6095G>A​(p.Arg2032Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: "SCV000214152: RT-PCR analysis performed on RNA isolated from an A-T individual with this alteration was reported to result in exon skipping (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79).; SCV000682303: Functional cytometric analysis of cells from individuals carrying this variant and affected with chronic lymphocytic leukemia showed decreased kinase activity (PMID:36029002).; SCV000218594: Studies have shown that this missense change results in skipping of exon 41 (also referred to as exon 43) , and produces a non-functional protein and/or introduces a premature termination codon (PMID:9887333; internal data).; SCV005625080: Functional studies demonstrated that this variant disrupted mRNA splicing resulting in premature termination of the protein (PMID:10330348 (1999), 9887333 (1999)).; SCV005876131: mRNA analyses revealed skipping of exon 41 (also known as exon 43) in lymphocytes derived from an affected individual (Sandoval 1999). PMID:9887333; SCV006325551: Studies performed on RNA isolated from an individual with A-T showed results in skipping of exon 41 (called exon 43 in the literature) and introduces a premature termination codon (PMID:9887333, 9443866, 10980530).; SCV000839886: Functional studies showed that this mutant causes abnormal splicing and loss of expression of ATM proteins [PMID:9887333, 10330348].; SCV004931300: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID:9887333, 10330348].". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2032S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29
• Conservation: PhyloP100: 9.47
• Publications: 39 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000214152: RT-PCR analysis performed on RNA isolated from an A-T individual with this alteration was reported to result in exon skipping (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79).; SCV000682303: Functional cytometric analysis of cells from individuals carrying this variant and affected with chronic lymphocytic leukemia showed decreased kinase activity (PMID: 36029002).; SCV000218594: Studies have shown that this missense change results in skipping of exon 41 (also referred to as exon 43) , and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9887333; internal data).; SCV005625080: Functional studies demonstrated that this variant disrupted mRNA splicing resulting in premature termination of the protein (PMID: 10330348 (1999), 9887333 (1999)).; SCV005876131: mRNA analyses revealed skipping of exon 41 (also known as exon 43) in lymphocytes derived from an affected individual (Sandoval 1999). PMID: 9887333; SCV006325551: Studies performed on RNA isolated from an individual with A-T showed results in skipping of exon 41 (called exon 43 in the literature) and introduces a premature termination codon (PMID: 9887333, 9443866, 10980530).; SCV000839886: Functional studies showed that this mutant causes abnormal splicing and loss of expression of ATM proteins [PMID: 9887333, 10330348].; SCV004931300: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 9887333, 10330348].
• 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 11-108315911-G-A is Pathogenic according to our data. Variant chr11-108315911-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 181974.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.6095G>A	p.Arg2032Lys	missense splice_region	Exon 41 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6095G>A	p.Arg2032Lys	missense splice_region	Exon 42 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-6840C>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.6095G>A	p.Arg2032Lys	missense splice_region	Exon 41 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6095G>A	p.Arg2032Lys	missense splice_region	Exon 42 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1159G>A		splice_region non_coding_transcript_exon	Exon 39 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251394 AF XY: 0.0000221

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458372 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725756

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1108846

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000393 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
7	-	-	Familial cancer of breast (7)
5	-	-	Ataxia-telangiectasia syndrome (5)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Adenocarcinoma (1)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	ATM-related cancer predisposition (1)
1	-	-	ATM-related disorder (1)
1	-	-	Breast carcinoma (1)
1	-	-	Carcinoma of pancreas (1)
1	-	-	Gastric cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.68
MVP		0.98
MPC		0.42
ClinPred		0.77	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.72
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		3.0
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.54		Position offset: 0

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

Other links and lift over

dbSNP: rs139770721; hg19: chr11-108186638;