chr5-74696744-G-A

Position:

chr5-74696744-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000521.4(HEXB):c.558+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000129 in 1,392,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HEXB
NM_000521.4 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.39

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:

HEXB (HGNC:):

HEXB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-74696744-G-A is Pathogenic according to our data. Variant chr5-74696744-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554107.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4 linkuse as main transcript	c.558+5G>A		splice_region_variant, intron_variant		ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 linkuse as main transcript	c.-118+5G>A		splice_region_variant, intron_variant			NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
HEXB	ENST00000261416.12 linkuse as main transcript	c.558+5G>A	splice_region_variant, intron_variant	1	NM_000521.4	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5 linkuse as main transcript	c.-118+5G>A	splice_region_variant, intron_variant	1		ENSP00000426285.1	Q5URX0
HEXB	ENST00000510820.1 linkuse as main transcript	n.277+5G>A	splice_region_variant, intron_variant	3
HEXB	ENST00000513079.5 linkuse as main transcript	n.623+5G>A	splice_region_variant, intron_variant	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1240712

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

628298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000175

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sandhoff disease

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2023	Variant summary: HEXB c.558+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, resulting in the skipping of exon 4 which leads to a premature truncation (Gaignard_2013). The variant was absent in 244516 control chromosomes (gnomAD). c.558+5G>A has been reported in the literature in one individual affected with Sandhoff Disease, who had a pathogenic variant in trans (Gaignard_2013). These data do not allow for an unequivocal conclusion about variant significance. The following publication has been ascertained in the context of this evaluation (PMID: 23046579). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=1)/likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	This sequence change falls in intron 4 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 23046579). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 554107). This variant has been observed in individual(s) with Sandhoff disease (PMID: 23046579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over