chr5-74715459-CT-C

Variant names:

• chr5-74715459-CT-C
• rs78084621
• NM_000521.4:c.902-48delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000521.4(HEXB):​c.902-48delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,267,100 control chromosomes in the GnomAD database, including 9,255 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1682 hom., cov: 30)
  • Exomes 𝑓: 0.11 (7573 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 5-74715459-CT-C is Benign according to our data. Variant chr5-74715459-CT-C is described in ClinVar as Benign. ClinVar VariationId is 256361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.198 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.902-48delT		intron	N/A	NP_000512.2
	HEXB	NM_001292004.2		c.227-48delT		intron	N/A	NP_001278933.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000261416.12	TSL:1 MANE Select	c.902-50delT		intron	N/A	ENSP00000261416.7
	HEXB	ENST00000511181.5	TSL:1	c.227-50delT		intron	N/A	ENSP00000426285.1
	HEXB	ENST00000504459.5	TSL:3	n.99-50delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20578 AN: 151954 Hom.: 1680 Cov.: 30

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.131 AC: 31367 AN: 239656 AF XY: 0.125

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.173

Gnomad FIN exome AF: 0.0523

Gnomad NFE exome AF: 0.0969

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.110 AC: 122759 AN: 1115028 Hom.: 7573 Cov.: 12 AF XY: 0.109 AC XY: 62408 AN XY: 571096

African (AFR) AF: 0.199 AC: 5247 AN: 26424

American (AMR) AF: 0.249 AC: 10603 AN: 42618

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2677 AN: 23686

East Asian (EAS) AF: 0.152 AC: 5812 AN: 38112

South Asian (SAS) AF: 0.121 AC: 9330 AN: 76820

European-Finnish (FIN) AF: 0.0529 AC: 2811 AN: 53154

Middle Eastern (MID) AF: 0.134 AC: 665 AN: 4958

European-Non Finnish (NFE) AF: 0.0995 AC: 79679 AN: 800442

Other (OTH) AF: 0.122 AC: 5935 AN: 48814

GnomAD4 genome AF: 0.136 AC: 20618 AN: 152072 Hom.: 1682 Cov.: 30 AF XY: 0.134 AC XY: 9994 AN XY: 74346

African (AFR) AF: 0.192 AC: 7952 AN: 41466

American (AMR) AF: 0.204 AC: 3109 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3468

East Asian (EAS) AF: 0.172 AC: 884 AN: 5152

South Asian (SAS) AF: 0.133 AC: 642 AN: 4822

European-Finnish (FIN) AF: 0.0499 AC: 529 AN: 10598

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.0990 AC: 6731 AN: 67988

Other (OTH) AF: 0.146 AC: 307 AN: 2106

Alfa AF: 0.118 Hom.: 211

Bravo AF: 0.152

Asia WGS AF: 0.175 AC: 609 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

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: rs78084621; hg19: chr5-74011284;