rs121907985

chr5-74720644-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000521.4(HEXB):c.1510C>T(p.Pro504Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P504P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: HEXB NM_000521.4 missense, splice_region
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.71

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 5-74720644-C-T is Pathogenic according to our data. Variant chr5-74720644-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.1510C>T	p.Pro504Ser	missense_variant, splice_region_variant	13/14	ENST00000261416.12
HEXB	NM_001292004.2	c.835C>T	p.Pro279Ser	missense_variant, splice_region_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.1510C>T	p.Pro504Ser	missense_variant, splice_region_variant	13/14	1	NM_000521.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251200 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461534 Hom.: 0 Cov.: 30 AF XY: 0.0000316 AC XY: 23 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74274

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000197

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: 0.0000373 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2022	Variant summary: HEXB c.1510C>T (p.Pro504Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 251200 control chromosomes. c.1510C>T has been reported in the literature as compound heterozygous genotypes in individuals affected with Sandhoff Disease (example, Hou_1998, Maegawa_2006, Tropak_2004, Alomso-Perez_2021, Masingue_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hou_1998). The most pronounced variant effect results in decreased level of heterodimer transport out of the endoplasmic reticulum by approx 45%, lowered heat stability, lowered ratio of units of ganglioside/ units of artificial substrate hydrolyzed, affects the ability of Hex A to hydrolyze its natural but not its artificial substrates. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 09, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HEXB c.1510C>T (p.Pro504Ser) variant was identified in the compound heterozygous state with the c.171delG (p.Trp57Cysfs7) variant in 1 individual with a history of muscle weakness and fasciculations in upper and lower limbs, and were confirmed to be in trans via sanger sequencing and segregation analysis (PMID: 34210542). The variant was also identified in the heterozygous state in two French Canadian sisters with Sandhoff disease alongside a 16-kb HEXB deletion on the other other allele (PMID: 9694901). The HEXB c.1510C>T has been previously reported to be associated with Sandhoff disease, as the variant decreases rate of heterodimer transport by approximately 45%, lowers heat stability, and impacts the ability of HEX A to hydrolyze its natural substrates (PMID: 9694901). The HEXB c.1510C>T (p.Pro504Ser) variant was identified in ClinVar (classified as likely pathogenic by Invitae, Natera Inc, and Women's Health and Genetics/Laboratory Corporation of America, LabCorp) and dbSNP (ID: rs121907985), but not COSMIC databases. The variant was identified in control databases in 10 of 282586 chromosomes (0 homozygous) at a frequency of 0.00003539, and was observed at the highest frequency in the Latino/Admixed American population in 8 of 35420 chromosomes (freq: 0.0002259) (Genome Aggregation Database November 15, 2022, v2.1.1). The p.Pro504 residue is conserved and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 504 of the HEXB protein (p.Pro504Ser). This variant is present in population databases (rs121907985, gnomAD 0.02%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 9694901, 34210542). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3884). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HEXB function (PMID: 9694901, 23127958). For these reasons, this variant has been classified as Pathogenic. -

Sandhoff disease, chronic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 14, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.98
MVP		1.0
MPC		0.72
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.010		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: rs121907985; hg19: chr5-74016469;