ENST00000567598.2:n.148T>C

Variant names:

• chr15-72376198-T-C
• rs4777505
• ENST00000567598.2:n.148T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000567598.2(HEXA-AS1):​n.148T>C 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 0.927 in 1,428,282 control chromosomes in the GnomAD database, including 621,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (54665 hom., cov: 34)
  • Exomes 𝑓: 0.94 (566935 hom.)
• Consequence: HEXA-AS1 ENST00000567598.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.137
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-72376198-T-C is Benign according to our data. Variant chr15-72376198-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

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-AS1	NR_027262.1		n.86T>C		non_coding_transcript_exon	Exon 1 of 1
	HEXA	NM_000520.6	MANE Select	c.-226A>G		upstream_gene	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.-226A>G		upstream_gene	N/A	NP_001305754.1	H3BP20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA-AS1	ENST00000567598.2	TSL:6	n.148T>C		non_coding_transcript_exon	Exon 1 of 1
	HEXA-AS1	ENST00000833226.1		n.106T>C		non_coding_transcript_exon	Exon 1 of 2
	HEXA-AS1	ENST00000833227.1		n.81T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.822 AC: 125112 AN: 152128 Hom.: 54658 Cov.: 34

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.981

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.952

Gnomad OTH AF: 0.856

GnomAD4 exome AF: 0.940 AC: 1199206 AN: 1276036 Hom.: 566935 Cov.: 57 AF XY: 0.941 AC XY: 582549 AN XY: 619186

African (AFR) AF: 0.478 AC: 13371 AN: 27964

American (AMR) AF: 0.933 AC: 18168 AN: 19468

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 18262 AN: 18604

East Asian (EAS) AF: 0.862 AC: 29463 AN: 34162

South Asian (SAS) AF: 0.951 AC: 58945 AN: 61954

European-Finnish (FIN) AF: 0.974 AC: 27979 AN: 28738

Middle Eastern (MID) AF: 0.921 AC: 3274 AN: 3556

European-Non Finnish (NFE) AF: 0.953 AC: 980816 AN: 1028692

Other (OTH) AF: 0.925 AC: 48928 AN: 52898

GnomAD4 genome AF: 0.822 AC: 125152 AN: 152246 Hom.: 54665 Cov.: 34 AF XY: 0.828 AC XY: 61656 AN XY: 74452

African (AFR) AF: 0.494 AC: 20478 AN: 41486

American (AMR) AF: 0.918 AC: 14058 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.981 AC: 3407 AN: 3472

East Asian (EAS) AF: 0.885 AC: 4574 AN: 5166

South Asian (SAS) AF: 0.947 AC: 4578 AN: 4832

European-Finnish (FIN) AF: 0.976 AC: 10374 AN: 10628

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.952 AC: 64787 AN: 68038

Other (OTH) AF: 0.857 AC: 1810 AN: 2112

Alfa AF: 0.910 Hom.: 78228

Bravo AF: 0.803

Asia WGS AF: 0.899 AC: 3126 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.45
PhyloP100		-0.14
PromoterAI		0.012	Neutral
Mutation Taster		=300/0	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: rs4777505; hg19: chr15-72668539;