rs770932296

Positions:

• chr15-72349266-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000520.6(HEXA):​c.806-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,612,286 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: HEXA NM_000520.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 0.443

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-72349266-C-T is Pathogenic according to our data. Variant chr15-72349266-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209160.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.806-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.839-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001305754.1
HEXA	NR_134869.3	n.848-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.806-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000520.6	ENSP00000268097	P1
	ENST00000570175.1	n.1578-958C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152190 Hom.: 0 Cov.: 32

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250368 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000443

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460096 Hom.: 0 Cov.: 31 AF XY: 0.0000716 AC XY: 52 AN XY: 726484

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000837

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000957 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tay-Sachs disease Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 09, 2021	NM_000520.4(HEXA):c.806-7G>A is an intronic variant classified as a variant of uncertain significance in the context of hexosaminidase A deficiency. c.806-7G>A has been observed in cases with relevant disease (PMID: 9272736). Functional assessments of this variant are available in the literature (PMID: 9272736). c.806-7G>A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000520.4(HEXA):c.806-7G>A as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 02, 2014	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [c.1073+1G>A] in a 25-year-old female with motor delay, hypotonia, scoliosis, progressive weakness, mild ankle contractures, mildly diminished sensation, gait abnormalities, sister possibly similarly symptomatic (not tested). Variant pathogenic in recessive state; heterozygotes are carriers. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2023	Variant summary: HEXA c.806-7G>A alters a non-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: Two predict the variant abolishes the canonical intron 7 - 3' splice acceptor site. Two predict the variant weakens the canonical intron 7 - 3' splice acceptor site. Three predict the variant creates a new intronic 3' splice acceptor site located 5 nucleotides upstream of the normal canonical intron 7 - 3' splice acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Fernandes_1997). The study demonstrated that this variant leads to a reduction in steady state levels of HEXA mRNA and production of an abnormally spliced mRNA species with exon 8 deleted. The variant allele was found at a frequency of 2.4e-05 in 250368 control chromosomes. c.806-7G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Tay-Sachs Disease (example, Fernandes_1997). The same publication also reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 5% of normal Hexosaminidase A enzyme activity measured in the fibroblasts of the individual with the compound heterozygous genotype. As a control measurement, the Hexosaminidase A enzyme activity in the fibroblasts of a carrier of the other allele was 57%, consistent with the carrier genotype. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as Likely Pathogenic (n=2)/Pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change falls in intron 7 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. This variant is present in population databases (rs770932296, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of Tay-Sachs disease (PMID: 9272736; Invitae; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 209160). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	Introduces a new splice acceptor site upstream of the normal intron 7 splice acceptor site and leads to a more than 80% reduction of steady-state HEXA mRNA levels (Fernandes et al., 1997); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17001642, 9272736, 26633545) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HEXA: PM3:Strong, PM2, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2019	The HEXA c.806-7G>A variant (rs770932296) is reported in the literature in an individual affected with chronic GM2-gangliosidosis that also carried a second pathogenic variant (Fernandes 1997). This variant is found on only seven chromosomes (7/281768 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Indeed, analyses of mRNAs from an individual carrying this variant indicates a >80% decrease in mRNA levels and skipping of exon 8 (Fernandes 1997). Based on available information, this variant is considered to be likely pathogenic. References: Fernandes MJ et al. A chronic GM2 gangliosidosis variant with a HEXA splicing defect: quantitation of HEXA mRNAs in normal and mutant fibroblasts. Eur J Hum Genet. 1997 May-Jun;5(3):129-36. -

Gm2-gangliosidosis, chronic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	20
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: -2
DS_AL_spliceai		0.44		Position offset: -7

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

Publications

LitVar

Other links and lift over

dbSNP: rs770932296; hg19: chr15-72641607;