NM_000521.4:c.300-32C>T

Variant names:

• chr5-74689296-C-T
• rs35711978
• NM_000521.4:c.300-32C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000521.4(HEXB):​c.300-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,585,054 control chromosomes in the GnomAD database, including 29,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4572 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25263 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.373
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-74689296-C-T is Benign according to our data. Variant chr5-74689296-C-T is described in ClinVar as Benign. ClinVar VariationId is 256356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.300-32C>T		intron	N/A	NP_000512.2
	HEXB	NM_001292004.2		c.-376-32C>T		intron	N/A	NP_001278933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000261416.12	TSL:1 MANE Select	c.300-32C>T		intron	N/A	ENSP00000261416.7
	HEXB	ENST00000511181.5	TSL:1	c.-376-32C>T		intron	N/A	ENSP00000426285.1
	HEXB	ENST00000513079.5	TSL:2	n.365-32C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34941 AN: 152010 Hom.: 4556 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.203 AC: 50815 AN: 250644 AF XY: 0.200

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.182 AC: 261191 AN: 1432928 Hom.: 25263 Cov.: 28 AF XY: 0.183 AC XY: 131059 AN XY: 714568

African (AFR) AF: 0.351 AC: 11486 AN: 32730

American (AMR) AF: 0.254 AC: 11333 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3627 AN: 25964

East Asian (EAS) AF: 0.164 AC: 6499 AN: 39558

South Asian (SAS) AF: 0.242 AC: 20742 AN: 85638

European-Finnish (FIN) AF: 0.166 AC: 8815 AN: 53028

Middle Eastern (MID) AF: 0.172 AC: 976 AN: 5676

European-Non Finnish (NFE) AF: 0.172 AC: 186572 AN: 1086198

Other (OTH) AF: 0.187 AC: 11141 AN: 59470

GnomAD4 genome AF: 0.230 AC: 34997 AN: 152126 Hom.: 4572 Cov.: 32 AF XY: 0.229 AC XY: 17043 AN XY: 74362

African (AFR) AF: 0.344 AC: 14257 AN: 41482

American (AMR) AF: 0.236 AC: 3606 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3468

East Asian (EAS) AF: 0.153 AC: 789 AN: 5170

South Asian (SAS) AF: 0.251 AC: 1211 AN: 4828

European-Finnish (FIN) AF: 0.174 AC: 1834 AN: 10562

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.177 AC: 12033 AN: 68020

Other (OTH) AF: 0.216 AC: 456 AN: 2112

Alfa AF: 0.199 Hom.: 641

Bravo AF: 0.241

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sandhoff disease Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.33
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35711978; hg19: chr5-73985121; COSMIC: COSV54666882; COSMIC: COSV54666882;