rs1555472543

Variant names:

• chr15-72347668-T-C
• rs1555472543
• NM_000520.6:c.1146+18A>G

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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

ENSG00000260729 (HGNC:):

ENSG00000261460 (HGNC:58304):

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 553551.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1146+18A>G		intron_variant	Intron 10 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1179+18A>G		intron_variant	Intron 10 of 13		NP_001305754.1
HEXA	NR_134869.3	n.1115+380A>G		intron_variant	Intron 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1146+18A>G		intron_variant	Intron 10 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-1343A>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1109814

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Sep 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Uncertain:1

Dec 21, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs1555472543; hg19: chr15-72640009;