rs1665894

Variant names:

• chr5-74696784-G-A
• rs1665894
• NM_000521.4:c.558+45G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-74696784-G-A
• chr5-74696784-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000521.4(HEXB):​c.558+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,003,202 control chromosomes in the GnomAD database, including 413,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60329 hom., cov: 33)
  • Exomes 𝑓: 0.91 (353640 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.08
• Publications: 9 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: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, Myriad Women's Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-74696784-G-A is Benign according to our data. Variant chr5-74696784-G-A is described in ClinVar as Benign. ClinVar VariationId is 256360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.918 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.558+45G>A		intron	N/A	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.-118+45G>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.558+45G>A		intron	N/A	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.-118+45G>A		intron	N/A	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000510820.1	TSL:3	n.277+45G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135267 AN: 152080 Hom.: 60279 Cov.: 33

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.948

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.877

GnomAD2 exomes AF: 0.890 AC: 188570 AN: 211900 AF XY: 0.896

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.774

Gnomad ASJ exome AF: 0.910

Gnomad EAS exome AF: 0.860

Gnomad FIN exome AF: 0.943

Gnomad NFE exome AF: 0.927

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.911 AC: 774943 AN: 851004 Hom.: 353640 Cov.: 11 AF XY: 0.911 AC XY: 406254 AN XY: 445710

African (AFR) AF: 0.843 AC: 17813 AN: 21142

American (AMR) AF: 0.781 AC: 32054 AN: 41058

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 19763 AN: 21738

East Asian (EAS) AF: 0.862 AC: 31164 AN: 36146

South Asian (SAS) AF: 0.899 AC: 63267 AN: 70370

European-Finnish (FIN) AF: 0.944 AC: 48546 AN: 51422

Middle Eastern (MID) AF: 0.889 AC: 4057 AN: 4562

European-Non Finnish (NFE) AF: 0.925 AC: 522333 AN: 564832

Other (OTH) AF: 0.905 AC: 35946 AN: 39734

GnomAD4 genome AF: 0.889 AC: 135372 AN: 152198 Hom.: 60329 Cov.: 33 AF XY: 0.888 AC XY: 66111 AN XY: 74408

African (AFR) AF: 0.844 AC: 35045 AN: 41512

American (AMR) AF: 0.823 AC: 12575 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3156 AN: 3472

East Asian (EAS) AF: 0.857 AC: 4439 AN: 5180

South Asian (SAS) AF: 0.891 AC: 4294 AN: 4818

European-Finnish (FIN) AF: 0.948 AC: 10056 AN: 10610

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.924 AC: 62821 AN: 68012

Other (OTH) AF: 0.879 AC: 1859 AN: 2116

Alfa AF: 0.904 Hom.: 11867

Bravo AF: 0.879

Asia WGS AF: 0.851 AC: 2933 AN: 3448

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.84
DANN	Benign	0.28
PhyloP100		-1.1
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1665894;

hg19: chr5-73992609;

COSMIC: COSV54667778;