rs114661695

Variant names:

• chr5-74715659-T-C
• rs114661695
• NM_000521.4:c.1051T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000521.4(HEXB):​c.1051T>C​(p.Leu351Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,608,682 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (79 hom.)
• Consequence: HEXB NM_000521.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.14
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.032).
• BP6: Variant 5-74715659-T-C is Benign according to our data. Variant chr5-74715659-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.006 (911/151880) while in subpopulation NFE AF = 0.00911 (619/67936). AF 95% confidence interval is 0.00852. There are 7 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1051T>C	p.Leu351Leu	synonymous	Exon 8 of 14	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.376T>C	p.Leu126Leu	synonymous	Exon 8 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.1051T>C	p.Leu351Leu	synonymous	Exon 8 of 14	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.376T>C	p.Leu126Leu	synonymous	Exon 8 of 14	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000513336.5	TSL:3	c.73T>C	p.Leu25Leu	synonymous	Exon 1 of 6	ENSP00000423713.1	H0Y9B6

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 911 AN: 151764 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00664

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00418

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00673 AC: 1690 AN: 251248 AF XY: 0.00697

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00394

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.00983

Gnomad OTH exome AF: 0.00947

GnomAD4 exome AF: 0.00818 AC: 11919 AN: 1456802 Hom.: 79 Cov.: 28 AF XY: 0.00819 AC XY: 5939 AN XY: 725010

African (AFR) AF: 0.00186 AC: 62 AN: 33394

American (AMR) AF: 0.00448 AC: 200 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 420 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00295 AC: 254 AN: 86090

European-Finnish (FIN) AF: 0.00416 AC: 222 AN: 53412

Middle Eastern (MID) AF: 0.0188 AC: 108 AN: 5744

European-Non Finnish (NFE) AF: 0.00913 AC: 10113 AN: 1107544

Other (OTH) AF: 0.00897 AC: 540 AN: 60226

GnomAD4 genome AF: 0.00600 AC: 911 AN: 151880 Hom.: 7 Cov.: 32 AF XY: 0.00539 AC XY: 400 AN XY: 74252

African (AFR) AF: 0.00159 AC: 66 AN: 41424

American (AMR) AF: 0.00663 AC: 101 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4810

European-Finnish (FIN) AF: 0.00418 AC: 44 AN: 10534

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00911 AC: 619 AN: 67936

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00793 Hom.: 7

Bravo AF: 0.00633

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Sandhoff disease (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.89
PhyloP100		2.1
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs114661695; hg19: chr5-74011484;