rs74020947

Variant names:

• chr15-72346046-G-C
• rs74020947
• ENST00000570175.1:n.826G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-72346046-G-C
• chr15-72346046-G-T

Variant summary

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

The ENST00000570175.1(ENSG00000261460):​n.826G>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 0.000676 in 627,374 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: ENSG00000261460 ENST00000570175.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 1 publications found

Genes affected

ENSG00000261460 (HGNC:58304):

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:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1421+189C>G		intron_variant	Intron 12 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1454+189C>G		intron_variant	Intron 12 of 13		NP_001305754.1
HEXA	NR_134869.3	n.1206+189C>G		intron_variant	Intron 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1421+189C>G		intron_variant	Intron 12 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.503+189C>G		intron_variant	Intron 4 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000441

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.000280 AC: 133 AN: 475046 Hom.: 1 Cov.: 4 AF XY: 0.000207 AC XY: 52 AN XY: 251208

African (AFR) AF: 0.00781 AC: 102 AN: 13062

American (AMR) AF: 0.000131 AC: 3 AN: 22870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14456

East Asian (EAS) AF: 0.00 AC: 0 AN: 31116

South Asian (SAS) AF: 0.0000417 AC: 2 AN: 47968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40806

Middle Eastern (MID) AF: 0.000500 AC: 1 AN: 2002

European-Non Finnish (NFE) AF: 0.0000290 AC: 8 AN: 276158

Other (OTH) AF: 0.000639 AC: 17 AN: 26608

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74490

African (AFR) AF: 0.00649 AC: 270 AN: 41584

American (AMR) AF: 0.000850 AC: 13 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.0000695 Hom.: 0

Bravo AF: 0.00239

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.89
DANN	Benign	0.48
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs74020947; hg19: chr15-72638387;