5-74685276-C-T

Variant names:

• chr5-74685276-C-T
• rs1580376985
• NM_000521.4:c.16C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000521.4(HEXB):​c.16C>T​(p.Leu6Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,389,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: HEXB NM_000521.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.203
• 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

ENSG00000306131 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-74685276-C-T is Benign according to our data. Variant chr5-74685276-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 793988.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.203 with no splicing effect.

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.16C>T	p.Leu6Leu	synonymous	Exon 1 of 14	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.-376-4052C>T		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.16C>T	p.Leu6Leu	synonymous	Exon 1 of 14	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.-376-4052C>T		intron	N/A	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000513079.5	TSL:2	n.81C>T		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1389090 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686164

African (AFR) AF: 0.0000322 AC: 1 AN: 31076

American (AMR) AF: 0.00 AC: 0 AN: 36434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24960

East Asian (EAS) AF: 0.0000559 AC: 2 AN: 35798

South Asian (SAS) AF: 0.00 AC: 0 AN: 79468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081212

Other (OTH) AF: 0.00 AC: 0 AN: 57772

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		0.20
PromoterAI		-0.013	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1580376985; hg19: chr5-73981101;