15-72350517-C-T

Variant names:

• chr15-72350517-C-T
• rs121907980
• ENST00000570175.1:n.1871C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000570175.1(ENSG00000261460):​n.1871C>T variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ENSG00000261460 ENST00000570175.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.81
• Publications: 4 publications found

Genes affected

ENSG00000261460 (HGNC:58304):

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

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 15-72350517-C-T is Pathogenic according to our data. Variant chr15-72350517-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.805+1G>A		splice_donor_variant, intron_variant	Intron 7 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.838+1G>A		splice_donor_variant, intron_variant	Intron 7 of 13		NP_001305754.1
HEXA	NR_134869.3	n.847+1G>A		splice_donor_variant, intron_variant	Intron 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.805+1G>A		splice_donor_variant, intron_variant	Intron 7 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-4192G>A		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251436 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000132 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:5 Other:1

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 22789865, 1483696 and 7717398. Classification of NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs121907980, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1483696, 22789865). It is commonly reported in individuals of French Canadian ancestry (PMID: 1483696). This variant is also known as IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 3938). 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. -

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1992

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 14, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HEXA c.805+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which is supported by a functional study (Hechtman_1992). In addition, Gort_2012 observed very little (<10%) HEXA activity in a compound heterozygote affected individual. This variant was found in 1/246234 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly French Canadians. In addition, a clinical diagnostic laboratory and reputable database classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

HEXA-related disorder Pathogenic:1

Feb 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HEXA c.805+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous state in multiple individuals with Tay-Sachs disease and was also shown to segregate with disease in three unrelated families (Figure 2, Hechtman et al. 1992. PubMed ID: 1483696; Table 2, Triggs-Raine et al. 1995. PubMed ID: 7717398; Table 1, Gort et al. 2012. PubMed ID: 22789865). Experimental studies suggest this variant impacts protein function showing little to no HexA activity in both serum and cultured human fibroblasts of the affected probands (Hechtman et al. 1992. PubMed ID: 1483696; Gort et al. 2012. PubMed ID: 22789865). This variant was found frequently in individuals of French Canadian ancestry (Hechtman et al. 1992. PubMed ID: 1483696). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in HEXA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.8
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs121907980; hg19: chr15-72642858;