5-74685139-C-T

Variant names:

• chr5-74685139-C-T
• rs1438020226
• ENST00000511181.5:c.-376-4189C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001292004.2(HEXB):​c.-376-4189C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000064 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: HEXB NM_001292004.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4189C>T		intron_variant	Intron 1 of 13		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000511181.5	c.-376-4189C>T		intron_variant	Intron 1 of 13	1		ENSP00000426285.1

Frequencies

GnomAD3 genomes AF: 0.0000641 AC: 2 AN: 31180 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000369

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000223 AC: 4 AN: 179726 Hom.: 0 Cov.: 0 AF XY: 0.0000337 AC XY: 3 AN XY: 89120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000589

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.0000641 AC: 2 AN: 31180 Hom.: 0 Cov.: 0 AF XY: 0.000131 AC XY: 2 AN XY: 15278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000369

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sandhoff disease Uncertain:1

Feb 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the HEXB gene. It does not change the encoded amino acid sequence of the HEXB protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HEXB-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Uncertain	0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1438020226; hg19: chr5-73980964;