rs121907960

chr15-72349147-TAAG-Tchr15-72349147-TAAG-TAAGAAG

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000520.6(HEXA):c.915_917del(p.Phe305del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: HEXA NM_000520.6 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.51

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a disulfide_bond (size 51) in uniprot entity HEXA_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000520.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000520.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 15-72349147-TAAG-T is Pathogenic according to our data. Variant chr15-72349147-TAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72349147-TAAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.915_917del	p.Phe305del	inframe_deletion	8/14	ENST00000268097.10
HEXA	NM_001318825.2	c.948_950del	p.Phe316del	inframe_deletion	8/14
HEXA	NR_134869.3	n.957_959del		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.915_917del	p.Phe305del	inframe_deletion	8/14	1	NM_000520.6	P1
	ENST00000570175.1	n.1578-1071_1578-1069del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152168 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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251444 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461728 Hom.: 0 AF XY: 0.0000701 AC XY: 51 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74462

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: 0.000282

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2021	Variant summary: HEXA c.915_917delCTT (p.Phe305del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 6.8e-05 in 251444 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (6.8e-05 vs 0.0014), allowing no conclusion about variant significance. c.915_917delCTT has been reported in the literature in multiple individuals affected with Tay-Sachs Disease, and has been reported as a common mutation in the Moroccan population (Navon_1991, Akli_1991, Montalvo_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant was reported to render the alpha-subunit enzymatically inactive (Montalvo_2005). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 05, 2014	- -
Affects, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This variant, c.915_917del, results in the deletion of 1 amino acid(s) of the HEXA protein (p.Phe305del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs778155650, gnomAD 0.03%). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 1322637, 1825014, 1837283, 16088929). It is commonly reported in individuals of Moroccan ancestry (PMID: 1322637, 1825014). This variant is also known as p.F304del. ClinVar contains an entry for this variant (Variation ID: 188812). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HEXA function (PMID: 1825014). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2023

Reported in multiple individuals with infantile-onset Tay Sachs disease who were either homozygous or compound heterozygous (Akli et al, 1991; Gort et al., 2012); Transfection in COS-1 cells of the mutant protein demonstrated an impairment in the alpha subunit of beta-hexosaminidase A, resulting in an absence of enzyme activity (Navon et al., 1991); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; This variant is associated with the following publications: (PMID: 1322637, 16088929, 22789865, 1825014, 1837283) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121907960; hg19: chr15-72641488;