NM_000520.6:c.459+5G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000520.6(HEXA):c.459+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000018 in 1,609,330 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.18

Publications

10 publications found

Variant links:

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]

HEXA Gene-Disease associations (from GenCC):

Tay-Sachs disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-72353686-C-T is Pathogenic according to our data. Variant chr15-72353686-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HEXA	NM_000520.6 link	c.459+5G>A	splice_region_variant, intron_variant	Intron 4 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 link	c.492+5G>A	splice_region_variant, intron_variant	Intron 4 of 13		NP_001305754.1
HEXA	NR_134869.3 link	n.501+5G>A	splice_region_variant, intron_variant	Intron 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.459+5G>A		splice_region_variant, intron_variant	Intron 4 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4 link	n.412+1873G>A		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.000478

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251424

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1457112

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725270

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33376

American (AMR)

AF:

0.000201

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000542

AC:

AN:

1107694

Other (OTH)

AF:

0.0000166

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.000589

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000585

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:6

Feb 09, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HEXA c.459+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 the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 2.8e-05 in 251424 control chromosomes. c.459+5G>A has been reported in the literature in multiple individuals affected with Tay-Sachs Disease (Gort_2012, Giraud_2010, Akli_1991). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22789865, 20100466, 1837283). ClinVar contains an entry for this variant (Variation ID: 374505). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 4 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs762060470, gnomAD 0.02%). This variant has been observed in individuals with Tay-Sachs disease (PMID: 1837283, 22441121, 22789865, 27896118). It is commonly reported in individuals of Spanish and Argentinian ancestry (PMID: 1837283, 22441121, 22789865, 27896118). This variant is also known as IVS4+5G>A. ClinVar contains an entry for this variant (Variation ID: 374505). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -

Mar 16, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 22, 2012

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:3

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP4, PM2, PM3_very_strong, PS4 -

Jul 07, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and functional analysis found this variant results in abnormal splicing (Akli et al., 1991); This variant is associated with the following publications: (PMID: 8044648, 27896118, 22441121, 25525159, 1837283, 9150157, 22723944, 24498621, 22789865, 34426522) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

5.2

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.63

Position offset: 5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over