15-72351132-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_000520.6(HEXA):​c.672+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000488 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: "SCV001442570: The variant allele was found at a frequency of 4e-06 in 251438 control chromosomes (gnomAD). c.672+1G>A has been reported in the literature in individuals affected with various forms (Juvenile/Adult, Late onset and Infantile acute) of Tay-Sachs Disease (Akli_1993, Maegawa_2007, Tanaka_2003). These data indicate that the variant may be associated with disease. Internal structural analysis indicates that this variant disrupts the characteristic motif of collagen and inserts a bulky sidechain into a sterically constrained region (Akli_1993). However, the actual output based on the instructions provided would be: no" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: HEXA NM_000520.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.81
• Publications: 3 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 16 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: SCV001442570: The variant allele was found at a frequency of 4e-06 in 251438 control chromosomes (gnomAD). c.672+1G>A has been reported in the literature in individuals affected with various forms (Juvenile/Adult, Late onset and Infantile acute) of Tay-Sachs Disease (Akli_1993, Maegawa_2007, Tanaka_2003). These data indicate that the variant may be associated with disease. Internal structural analysis indicates that this variant disrupts the characteristic motif of collagen and inserts a bulky sidechain into a sterically constrained region (Akli_1993). However, the actual output based on the instructions provided would be: no; SCV002162125: Disruption of this splice site has been observed in individual(s) with clinical features of hexosaminidase A deficiency (PMID: 14566483, 17015493).; SCV000521179: cDNA and Northern blot analyses found that c.672+1 G>A results in skipping of exon 6 and a 50% reduction in HEXA mRNA levels (Akli et al. 1993).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72351132-C-T is Pathogenic according to our data. Variant chr15-72351132-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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>A		splice_donor intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.705+1G>A		splice_donor intron	N/A	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.714+1G>A		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>A		splice_donor intron	N/A	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.672+1G>A		splice_donor intron	N/A	ENSP00000456489.1	H3BS10
	CELF6-AS1	ENST00000570175.1	TSL:1	n.2486C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251438 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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1433838 Hom.: 0 Cov.: 27 AF XY: 0.00000699 AC XY: 5 AN XY: 715296

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: 0.00000552 AC: 6 AN: 1086426

Other (OTH) AF: 0.0000168 AC: 1 AN: 59474

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Tay-Sachs disease (4)
1	-	-	not provided (1)
1	-	-	TAY-SACHS DISEASE, JUVENILE/ADULT (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	30
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 (ClinVar)

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;