rs1555472543

chr15-72347668-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000520.6(HEXA):c.1146+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,459,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.199

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-72347668-T-C is Benign according to our data. Variant chr15-72347668-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553551.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1146+18A>G		intron_variant		ENST00000268097.10
HEXA	NM_001318825.2	c.1179+18A>G		intron_variant
HEXA	NR_134869.3	n.1115+380A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1146+18A>G		intron_variant		1	NM_000520.6	P1
	ENST00000570175.1	n.1577+871T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1459476 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726328

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tay-Sachs disease Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 21, 2020

The HEXA c.1146+18A>G variant (rs1555472543) is reported in the literature in the heterozygous state in individuals with enzyme levels consistent with carrier status for Tay-Sachs disease (Martin 2007, Triggs-Raine 1995). This variant is also reported in ClinVar (Variation ID: 553551), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant does not alter splicing. However, given the lack of clinical and functional data, the significance of the c.1146+18A>G variant is uncertain at this time. References: Martin DC et al. Evaluation of the risk for Tay-Sachs disease in individuals of French Canadian ancestry living in new England. Clin Chem. 2007 Mar;53(3):392-8. Triggs-Raine B et al. Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of French Canadian background living in New England. Am J Hum Genet. 1995 Apr;56(4):870-9. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.9
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1555472543; hg19: chr15-72640009;