NM_000521.4:c.362A>G

Variant names:

• chr5-74689390-A-G
• rs11556045
• NM_000521.4:c.362A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000521.4(HEXB):​c.362A>G​(p.Lys121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,611,362 control chromosomes in the GnomAD database, including 28,987 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3527 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25460 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.903
• Publications: 45 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a disulfide_bond (size 46) in uniprot entity HEXB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000521.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050745904).
• BP6: Variant 5-74689390-A-G is Benign according to our data. Variant chr5-74689390-A-G is described in ClinVar as Benign. ClinVar VariationId is 3874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 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.362A>G	p.Lys121Arg	missense	Exon 2 of 14	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.-314A>G		5_prime_UTR	Exon 2 of 14	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.362A>G	p.Lys121Arg	missense	Exon 2 of 14	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.-314A>G		5_prime_UTR	Exon 2 of 14	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000513079.5	TSL:2	n.427A>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31633 AN: 152046 Hom.: 3521 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.228

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: 0.201

GnomAD2 exomes AF: 0.197 AC: 49605 AN: 251398 AF XY: 0.196

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.183 AC: 266797 AN: 1459198 Hom.: 25460 Cov.: 30 AF XY: 0.184 AC XY: 133645 AN XY: 726094

African (AFR) AF: 0.278 AC: 9304 AN: 33416

American (AMR) AF: 0.250 AC: 11196 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3676 AN: 26122

East Asian (EAS) AF: 0.165 AC: 6549 AN: 39686

South Asian (SAS) AF: 0.243 AC: 20954 AN: 86180

European-Finnish (FIN) AF: 0.167 AC: 8895 AN: 53412

Middle Eastern (MID) AF: 0.168 AC: 967 AN: 5766

European-Non Finnish (NFE) AF: 0.175 AC: 194077 AN: 1109586

Other (OTH) AF: 0.185 AC: 11179 AN: 60310

GnomAD4 genome AF: 0.208 AC: 31673 AN: 152164 Hom.: 3527 Cov.: 32 AF XY: 0.208 AC XY: 15501 AN XY: 74384

African (AFR) AF: 0.268 AC: 11110 AN: 41500

American (AMR) AF: 0.228 AC: 3479 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3470

East Asian (EAS) AF: 0.152 AC: 786 AN: 5166

South Asian (SAS) AF: 0.251 AC: 1211 AN: 4826

European-Finnish (FIN) AF: 0.174 AC: 1843 AN: 10598

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12011 AN: 68002

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.185 Hom.: 10610

Bravo AF: 0.216

TwinsUK AF: 0.177 AC: 656

ALSPAC AF: 0.183 AC: 705

ESP6500AA AF: 0.259 AC: 1141

ESP6500EA AF: 0.169 AC: 1452

ExAC AF: 0.199 AC: 24137

Asia WGS AF: 0.227 AC: 789 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.177

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Sandhoff disease (5)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	HEXB POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.056
DANN	Benign	0.33
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0035	N
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.90
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.21
Sift	Benign	0.63	T
Sift4G	Benign	0.61	T
Vest4		0.011
MPC		0.14
ClinPred		0.0013	T
GERP RS		-7.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.29
Mutation Taster		=98/2	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: rs11556045; hg19: chr5-73985215; COSMIC: COSV54666892; COSMIC: COSV54666892;