rs112626309

Variant names:

• chr15-72343641-G-A
• rs112626309
• NM_000520.6:c.*436C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000520.6(HEXA):​c.*436C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 239,802 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: HEXA NM_000520.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.117
• Publications: 1 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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ENSG00000260729 (HGNC:):

CELF6-AS1 (HGNC:58304):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.*436C>T		3_prime_UTR	Exon 14 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.*436C>T		3_prime_UTR	Exon 14 of 14	NP_001305754.1	H3BP20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.*436C>T		3_prime_UTR	Exon 14 of 14	ENSP00000268097.6	P06865-1
	ENSG00000260729	ENST00000379915.4	TSL:2	n.608+1805C>T		intron	N/A	ENSP00000478716.1	A0A087WUJ7
	CELF6-AS1	ENST00000570175.1	TSL:1	n.166-1745G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000217 AC: 19 AN: 87684 Hom.: 0 Cov.: 0 AF XY: 0.000218 AC XY: 10 AN XY: 45974

African (AFR) AF: 0.00174 AC: 6 AN: 3454

American (AMR) AF: 0.000400 AC: 2 AN: 5004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2040

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 12476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3330

Middle Eastern (MID) AF: 0.00318 AC: 1 AN: 314

European-Non Finnish (NFE) AF: 0.000136 AC: 7 AN: 51456

Other (OTH) AF: 0.000658 AC: 3 AN: 4556

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74350

African (AFR) AF: 0.000867 AC: 36 AN: 41504

American (AMR) AF: 0.000458 AC: 7 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000495

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Tay-Sachs disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.62
PhyloP100		-0.12

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: rs112626309; hg19: chr15-72635982;