ENST00000567598.2:n.58C>G

Variant names:

• chr15-72376108-C-G
• rs561320483
• ENST00000567598.2:n.58C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000567598.2(HEXA-AS1):​n.58C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,352,986 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HEXA-AS1 ENST00000567598.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.706
• Publications: 0 publications found

Genes affected

HEXA-AS1 (HGNC:25810): (HEXA antisense RNA 1)

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:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000567598.2. 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.-136G>C		upstream_gene	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.-136G>C		upstream_gene	N/A	NP_001305754.1	H3BP20
	HEXA-AS1	NR_027262.1		n.-5C>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA-AS1	ENST00000567598.2	TSL:6	n.58C>G		non_coding_transcript_exon	Exon 1 of 1
	HEXA-AS1	ENST00000833226.1		n.16C>G		non_coding_transcript_exon	Exon 1 of 2
	HEXA	ENST00000569509.5	TSL:4	n.146+167G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1352986 Hom.: 0 Cov.: 31 AF XY: 0.00000300 AC XY: 2 AN XY: 666682

African (AFR) AF: 0.00 AC: 0 AN: 30116

American (AMR) AF: 0.00 AC: 0 AN: 28006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22164

East Asian (EAS) AF: 0.00 AC: 0 AN: 36226

South Asian (SAS) AF: 0.00 AC: 0 AN: 75792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3768

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1067754

Other (OTH) AF: 0.00 AC: 0 AN: 56028

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.3
DANN	Benign	0.64
PhyloP100		-0.71
PromoterAI		-0.090	Neutral

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: rs561320483; hg19: chr15-72668449;