rs148268937

Positions:

• chr5-74693642-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000521.4(HEXB):​c.449C>A​(p.Thr150Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,609,124 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (19 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0700

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047442913).
• BP6: Variant 5-74693642-C-A is Benign according to our data. Variant chr5-74693642-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 235583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00896 (1364/152260) while in subpopulation AFR AF= 0.0308 (1281/41540). AF 95% confidence interval is 0.0294. There are 27 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4	c.449C>A	p.Thr150Asn	missense_variant	3/14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.-227C>A		5_prime_UTR_variant	3/14		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.449C>A	p.Thr150Asn	missense_variant	3/14	1	NM_000521.4	ENSP00000261416.7
HEXB	ENST00000511181	c.-227C>A		5_prime_UTR_variant	3/14	1		ENSP00000426285.1
HEXB	ENST00000510820.1	n.168C>A		non_coding_transcript_exon_variant	1/4	3
HEXB	ENST00000513079.5	n.514C>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.00895 AC: 1362 AN: 152142 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

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: 0.000103

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00253 AC: 636 AN: 251488 Hom.: 15 AF XY: 0.00178 AC XY: 242 AN XY: 135918

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000958 AC: 1395 AN: 1456864 Hom.: 19 Cov.: 29 AF XY: 0.000786 AC XY: 570 AN XY: 725114

Gnomad4 AFR exome AF: 0.0307

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00896 AC: 1364 AN: 152260 Hom.: 27 Cov.: 32 AF XY: 0.00835 AC XY: 622 AN XY: 74452

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00167 Hom.: 4

Bravo AF: 0.0105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0318 AC: 140

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00306 AC: 372

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sandhoff disease Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.2
DANN	Benign	0.89
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.71	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.16	T
Sift4G	Benign	0.35	T
Vest4		0.11
MVP		0.64
MPC		0.20
ClinPred		0.00088	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs148268937; hg19: chr5-73989467;