rs114661695

Positions:

• chr5-74715659-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000521.4(HEXB):​c.1051T>C​(p.Leu351=) 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

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-74715659-T-C is Benign according to our data. Variant chr5-74715659-T-C is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.1051T>C	p.Leu351=	synonymous_variant	8/14	ENST00000261416.12
HEXB	NM_001292004.2	c.376T>C	p.Leu126=	synonymous_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.1051T>C	p.Leu351=	synonymous_variant	8/14	1	NM_000521.4	P1

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

GnomAD3 exomes AF: 0.00673 AC: 1690 AN: 251248 Hom.: 11 AF XY: 0.00697 AC XY: 947 AN XY: 135814

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 SAS exome AF: 0.00258

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

Gnomad4 AFR exome AF: 0.00186

Gnomad4 AMR exome AF: 0.00448

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.00416

Gnomad4 NFE exome AF: 0.00913

Gnomad4 OTH exome AF: 0.00897

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

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00663

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00418

Gnomad4 NFE AF: 0.00911

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00871 Hom.: 6

Bravo AF: 0.00633

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.0103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HEXB: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs114661695; hg19: chr5-74011484;