Genetic Variant HEXB:p.Leu6Leu (chr5-74685276-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_000521.4(HEXB):c.16C>T(p.Leu6Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,389,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

HEXB
NM_000521.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.203

Variant links:

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 links:

ENSG00000306131 (HGNC:):

ENSG00000306131 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-74685276-C-T is Benign according to our data. Variant chr5-74685276-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 793988.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.203 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.16C>T	p.Leu6Leu	synonymous_variant	Exon 1 of 14	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.-376-4052C>T		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 link	c.16C>T	p.Leu6Leu	synonymous_variant	Exon 1 of 14	1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1389090

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686164

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31076

American (AMR)

AF:

0.00

AC:

AN:

36434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24960

East Asian (EAS)

AF:

0.0000559

AC:

AN:

35798

South Asian (SAS)

AF:

0.00

AC:

AN:

79468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081212

Other (OTH)

AF:

0.00

AC:

AN:

57772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:1

Mar 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.20

PromoterAI

-0.013

Neutral

(source)

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

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5-74685276-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over