ENST00000570175.1:n.830T>C

Variant names:

• chr15-72346050-T-C
• rs57733983
• ENST00000570175.1:n.830T>C

Variant summary

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

The ENST00000570175.1(ENSG00000261460):​n.830T>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 0.00954 in 630,202 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (34 hom.)
• Consequence: ENSG00000261460 ENST00000570175.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-72346050-T-C is Benign according to our data. Variant chr15-72346050-T-C is described in ClinVar as [Benign]. Clinvar id is 1252412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1421+185A>G		intron_variant	Intron 12 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1454+185A>G		intron_variant	Intron 12 of 13		NP_001305754.1
HEXA	NR_134869.3	n.1206+185A>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+185A>G		intron_variant	Intron 12 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.503+185A>G		intron_variant	Intron 4 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2893 AN: 152136 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00652 AC: 3118 AN: 477948 Hom.: 34 Cov.: 4 AF XY: 0.00605 AC XY: 1529 AN XY: 252880

African (AFR) AF: 0.0515 AC: 672 AN: 13060

American (AMR) AF: 0.00613 AC: 141 AN: 22992

Ashkenazi Jewish (ASJ) AF: 0.0000686 AC: 1 AN: 14568

East Asian (EAS) AF: 0.00 AC: 0 AN: 31182

South Asian (SAS) AF: 0.000145 AC: 7 AN: 48144

European-Finnish (FIN) AF: 0.00197 AC: 82 AN: 41716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2018

European-Non Finnish (NFE) AF: 0.00715 AC: 1984 AN: 277526

Other (OTH) AF: 0.00864 AC: 231 AN: 26742

GnomAD4 genome AF: 0.0190 AC: 2897 AN: 152254 Hom.: 63 Cov.: 32 AF XY: 0.0179 AC XY: 1335 AN XY: 74454

African (AFR) AF: 0.0531 AC: 2206 AN: 41536

American (AMR) AF: 0.0101 AC: 154 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 68016

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.0137 Hom.: 8

Bravo AF: 0.0210

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 01, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.26
DANN	Benign	0.40
PhyloP100		-1.6
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)		0.010		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: rs57733983; hg19: chr15-72638391;