chr11-108331877-A-C

Variant names:

• chr11-108331877-A-C
• rs587779866
• NM_000051.4:c.7630-2A>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Moderate PS3 PP5_Very_Strong

The NM_000051.4(ATM):​c.7630-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,150 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000183992: This variant has been identified in conjunction with other ATM variant(s) in individuals(s) with features consistent with ataxia telangiectasia and has been shown to result in aberrant splicing and decreased ATM protein levels (Sandoval N et al. Hum. Mol. Genet. 1999 Jan" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ATM NM_000051.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:28 O:1
• Conservation: PhyloP100: 7.35
• Publications: 34 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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017337259 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 11, new splice context is: ttcttaccgctaatctctAGaat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000183992: This variant has been identified in conjunction with other ATM variant(s) in individuals(s) with features consistent with ataxia telangiectasia and has been shown to result in aberrant splicing and decreased ATM protein levels (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Teraoka S et al. Am J Hum Genet. 1999 Jun;64(6):1617-31; Coutinho G et al. Am. J. Med. Genet. A. 2004 Apr;126A:33-40; Soukupova J et al. Neuromolecular Med. 2011 Sep;13:204-11; Nespoli L et al. Case Reports Immunol, 2013 Oct;2013:296827; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11;). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV000537667: This variant has been shown to cause aberrant RNA splicing and result in the absence of ATM protein (PMID: 9887333, 35716007).; SCV000821703: An experimental study showed that this variant results in two aberrant forms of the ATM transcript, one in which exon 52 is skipped and another in which the first 11 nucleotides of exons 52 are skipped (PMID: 9887333 ).; SCV000260235: Studies have shown that disruption of this splice site results in skipping of exon 52 and activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9887333; internal data).; SCV001360530: The variant allele was found at a frequency of 8e-06 in 251132 control chromosomes. c.7630-2A>C has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as well as in individuals undergoing multigene panel testing for hereditary cancers (example, Sandoval_1999). The variant allele was found at a frequency of 8e-06 in 251132 control chromosomes. c.7630-2A>C has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as well as in individuals undergoing multigene panel testing for hereditary cancers (legacy exon numbering) (Sandoval_1999). Since the provided text does not explicitly mention functional studies but rather focuses on the frequency of the variant and its association with disease, the correct response based on the instructions is: `no`; SCV005626304: A study in cell lines indicated this variant causes exon skipping, and no detectable ATM protein was observed in the homozygous case (PMID: 9887333 (1999)).; SCV004931097: Functional studies indicate this variant impacts protein function [PMID: 9443866, 9887333, 10330348].
• PP5: Variant 11-108331877-A-C is Pathogenic according to our data. Variant chr11-108331877-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 127447.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.7630-2A>C		splice_acceptor intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.7630-2A>C		splice_acceptor intron	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-22806T>G		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.7630-2A>C		splice_acceptor intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7630-2A>C		splice_acceptor intron	N/A	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1270-310T>G		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251132 AF XY: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460998 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726852

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111344

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000771 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Ataxia-telangiectasia syndrome (8)
6	-	-	Familial cancer of breast (6)
6	-	-	not provided (6)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (2)
1	-	-	ATM-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Colorectal cancer (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.3
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.53		Position offset: 13
DS_AL_spliceai		0.91		Position offset: 2

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

Other links and lift over

dbSNP: rs587779866; hg19: chr11-108202604; COSMIC: COSV105124714;