11-108312424-G-T

Variant names:

• chr11-108312424-G-T
• rs587779852
• NM_000051.4:c.5932G>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PVS1 PS3 PP3 PP5_Very_Strong

The NM_000051.4(ATM):​c.5932G>T​(p.Glu1978*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,595,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002064361: Functional studies have demonstrated skipping of exon 40 in the presence of this sequence change (PMIDs: 9443866, 10330348, 24451234)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1978E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:33 O:1
• Conservation: PhyloP100: 8.65
• Publications: 74 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 21 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: SCV002064361: Functional studies have demonstrated skipping of exon 40 in the presence of this sequence change (PMIDs: 9443866, 10330348, 24451234).; SCV001434995: Experimental studies indicate that this nonsense change leads to out-of-frame skipping of exon 41 (PMID: 10330348, 24451234).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108312424-G-T is Pathogenic according to our data. Variant chr11-108312424-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 127414.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.5932G>T	p.Glu1978*	stop_gained	Exon 40 of 63	NP_000042.3
	ATM	NM_001351834.2		c.5932G>T	p.Glu1978*	stop_gained	Exon 41 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-3353C>A		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.5932G>T	p.Glu1978*	stop_gained	Exon 40 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.5932G>T	p.Glu1978*	stop_gained	Exon 41 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*996G>T		non_coding_transcript_exon	Exon 38 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152150 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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251182 AF XY: 0.0000368

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: 0.0000880

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1443140 Hom.: 0 Cov.: 29 AF XY: 0.0000139 AC XY: 10 AN XY: 719082

African (AFR) AF: 0.00 AC: 0 AN: 33030

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000192 AC: 21 AN: 1095238

Other (OTH) AF: 0.0000167 AC: 1 AN: 59770

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000461 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3472

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Ataxia-telangiectasia syndrome (8)
8	-	-	Familial cancer of breast (8)
8	-	-	not provided (8)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (3)
2	-	-	Breast and/or ovarian cancer (2)
1	-	-	Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to (1)
1	-	-	ATM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.6
Vest4		0.94
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.61		Position offset: -13

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

Other links and lift over

dbSNP: rs587779852; hg19: chr11-108183151;