rs387906311

Variant names:

• chr15-72351132-C-A
• rs387906311
• NM_000520.6:c.672+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-72351132-C-A
• chr15-72351132-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_000520.6(HEXA):​c.672+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,838 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: "SCV004548936: Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID:8490625).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HEXA NM_000520.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

HEXA Gene-Disease associations (from GenCC):

• Tay-Sachs disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

CELF6-AS1 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.064150944 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004548936: Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 8490625).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72351132-C-A is Pathogenic according to our data. Variant chr15-72351132-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2914532.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. 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
	HEXA	NM_000520.6	MANE Select	c.672+1G>T		splice_donor intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.705+1G>T		splice_donor intron	N/A	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.714+1G>T		splice_donor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.672+1G>T		splice_donor intron	N/A	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.672+1G>T		splice_donor intron	N/A	ENSP00000456489.1	H3BS10
	CELF6-AS1	ENST00000570175.1	TSL:1	n.2486C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433838 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 715296

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32904

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086426

Other (OTH) AF: 0.00 AC: 0 AN: 59474

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Tay-Sachs disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.8
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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

Other links and lift over

dbSNP: rs387906311; hg19: chr15-72643473; COSMIC: COSV51509016; COSMIC: COSV51509016;