rs121907984

Positions:

• chr5-74721131-G-A
• chr5-74721131-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000521.4(HEXB):​c.1627G>A​(p.Ala543Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00048 in 1,612,544 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Synonymous variant affecting the same amino acid position (i.e. A543A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (13 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 7.04

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000521.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.061395913).
• BP6: Variant 5-74721131-G-A is Benign according to our data. Variant chr5-74721131-G-A is described in ClinVar as [Likely_benign, other]. Clinvar id is 3881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74721131-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000315 (48/152216) while in subpopulation SAS AF= 0.00623 (30/4818). AF 95% confidence interval is 0.00448. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.1627G>A	p.Ala543Thr	missense_variant	14/14	ENST00000261416.12
HEXB	NM_001292004.2	c.952G>A	p.Ala318Thr	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.1627G>A	p.Ala543Thr	missense_variant	14/14	1	NM_000521.4	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000860 AC: 216 AN: 251138 Hom.: 3 AF XY: 0.00119 AC XY: 162 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000497 AC: 726 AN: 1460328 Hom.: 13 Cov.: 29 AF XY: 0.000666 AC XY: 484 AN XY: 726546

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00609

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74426

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000213 Hom.: 1

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 18, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -

not provided Benign:1 Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2016	Variant summary: The HEXB c.1627G>A (p.Ala543Thr) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 115/120804 (1/1052, 1 homozygote), predominantly observed in the South Asian cohort, 92/16490 (1/179, 1 homozygote), which exceeds the estimated maximal expected allele frequency for a pathogenic HEXB variant of 1/676. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has been reported in multiple affected and healthy homozygous individuals via publications. Functional studies have shown that the variant of interest is a heat labile allele, meaning that it leads to reduction in enzyme activity and mightresult in a false non-TSD or non-SD diagnosis. Likewise, a doubly heterozygous person, for TSD and for HLB, could be misdiagnosed as a normal homozygote. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "benign," along with the reporting cautionary awareness for the heat labile aspect. Therefore, to indicate the potential for the variant to cause false negative results, a classification of "Probable Normal Variant/Likely Benign," has been assigned to this variant. -

HEXOSAMINIDASE B, HEAT-LABILE POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Vest4		0.78
MVP		0.98
MPC		0.66
ClinPred		0.24	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121907984; hg19: chr5-74016956; COSMIC: COSV54669283; COSMIC: COSV54669283;