rs12593333

Variant names:

• chr15-72347294-G-A
• rs12593333
• NM_000520.6:c.1146+392C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-72347294-G-A
• chr15-72347294-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000520.6(HEXA):​c.1146+392C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.90 (60258 hom., cov: 20)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.881
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1146+392C>T		intron_variant	Intron 10 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1179+392C>T		intron_variant	Intron 10 of 13		NP_001305754.1
HEXA	NR_134869.3	n.1115+754C>T		intron_variant	Intron 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1146+392C>T		intron_variant	Intron 10 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-969C>T		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.901 AC: 129898 AN: 144242 Hom.: 60235 Cov.: 20

Gnomad AFR AF: 0.660

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.965

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.980

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.932

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.900 AC: 129973 AN: 144356 Hom.: 60258 Cov.: 20 AF XY: 0.902 AC XY: 62581 AN XY: 69346

African (AFR) AF: 0.660 AC: 26494 AN: 40118

American (AMR) AF: 0.965 AC: 13357 AN: 13840

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3397 AN: 3398

East Asian (EAS) AF: 1.00 AC: 4842 AN: 4842

South Asian (SAS) AF: 0.999 AC: 4201 AN: 4206

European-Finnish (FIN) AF: 0.996 AC: 8878 AN: 8910

Middle Eastern (MID) AF: 0.979 AC: 274 AN: 280

European-Non Finnish (NFE) AF: 0.998 AC: 65821 AN: 65920

Other (OTH) AF: 0.932 AC: 1833 AN: 1966

Alfa AF: 0.931 Hom.: 8678

Bravo AF: 0.890

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.84
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism (auto)

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: rs12593333; hg19: chr15-72639635;