rs779273534

Variant names:

• chr5-74720760-T-TTAAG
• rs779273534
• NM_000521.4:c.1613+15_1613+18dupAAGT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_000521.4(HEXB):​c.1613+15_1613+18dupAAGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,587,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002015171: The variant was absent in 250692 control chromosomes. c.1613+15_1613+18dupAAGT has been reported in the literature as a compound heterozygous genotype and as a homozygous genotype respectively in at-least two individuals, one of whom was affected with Juvenile-onset motor neuron disease (compound heterozygote, Pierson_2013). The authors also noted the presence of normal cDNA products indicating that the mRNA produced from this allele likely underwent some degree of proper splicing resulting in a small fraction of normal beta subunits as well. The report by Pierson_2013, also noted a very small amount of wild-type beta-subunit protein (approximately 5% of normal) and a skweing of the total HEX A activity towards the HEX-A and/or HEX S isoforms. The authors speculate that the residual low amounts of mature beta subunit protein could explain the patient's later-onset phenotype as compared to the more fulminant infantile variant of Sandhoff disease. PMID:24076290".

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: -0.614
• Publications: 0 publications found

Genes affected

HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

HEXB Gene-Disease associations (from GenCC):

• Sandhoff disease

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002015171: The variant was absent in 250692 control chromosomes. c.1613+15_1613+18dupAAGT has been reported in the literature as a compound heterozygous genotype and as a homozygous genotype respectively in at-least two individuals, one of whom was affected with Juvenile-onset motor neuron disease (compound heterozygote, Pierson_2013). The authors also noted the presence of normal cDNA products indicating that the mRNA produced from this allele likely underwent some degree of proper splicing resulting in a small fraction of normal beta subunits as well. The report by Pierson_2013, also noted a very small amount of wild-type beta-subunit protein (approximately 5% of normal) and a skweing of the total HEX A activity towards the HEX-A and/or HEX S isoforms. The authors speculate that the residual low amounts of mature beta subunit protein could explain the patient's later-onset phenotype as compared to the more fulminant infantile variant of Sandhoff disease. PMID:24076290
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-74720760-T-TTAAG is Pathogenic according to our data. Variant chr5-74720760-T-TTAAG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 555459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000521.4. 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
	HEXB	NM_000521.4	MANE Select	c.1613+15_1613+18dupAAGT		intron	N/A	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.938+15_938+18dupAAGT		intron	N/A	NP_001278933.1	Q5URX0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000261416.12	TSL:1 MANE Select	c.1613+15_1613+18dupAAGT		intron	N/A	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.938+15_938+18dupAAGT		intron	N/A	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000513336.5	TSL:3	c.548+15_548+18dupAAGT		intron	N/A	ENSP00000423713.1	H0Y9B6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 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

GnomAD4 exome AF: 0.0000780 AC: 112 AN: 1435000 Hom.: 0 Cov.: 26 AF XY: 0.0000671 AC XY: 48 AN XY: 715674

African (AFR) AF: 0.0000303 AC: 1 AN: 32966

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 85674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000993 AC: 108 AN: 1087638

Other (OTH) AF: 0.0000504 AC: 3 AN: 59500

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Sandhoff disease (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.61
Mutation Taster		=32/68	disease causing

Splicing

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

Other links and lift over

dbSNP: rs779273534; hg19: chr5-74016585;