5-74685280-G-A

Variant names:

• chr5-74685280-G-A
• rs1029681294
• NM_000521.4:c.20G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000521.4(HEXB):​c.20G>A​(p.Gly7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G7G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.546
• Publications: 1 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

ENSG00000306131 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122680426).

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.20G>A	p.Gly7Glu	missense	Exon 1 of 14	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.-376-4048G>A		intron	N/A	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.20G>A	p.Gly7Glu	missense	Exon 1 of 14	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.-376-4048G>A		intron	N/A	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000513079.5	TSL:2	n.85G>A		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000139 AC: 2 AN: 143816 AF XY: 0.0000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 2 AN: 1392464 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 687956

African (AFR) AF: 0.00 AC: 0 AN: 31350

American (AMR) AF: 0.00 AC: 0 AN: 36810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 36058

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4368

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082486

Other (OTH) AF: 0.00 AC: 0 AN: 57894

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Sandhoff disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.97
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.018	N
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.096	D
PhyloP100		-0.55
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.043	D
Vest4		0.16
MutPred		0.39		Loss of helix (P = 0.028)
MVP		0.84
MPC		0.23
ClinPred		0.14	T
GERP RS		1.7
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
gMVP		0.72
Mutation Taster		=97/3	polymorphism

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: rs1029681294; hg19: chr5-73981105;