NM_000520.6:c.1074-43C>G

Variant names:

• chr15-72347801-G-C
• rs16956759
• NM_000520.6:c.1074-43C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000520.6(HEXA):​c.1074-43C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,573,718 control chromosomes in the GnomAD database, including 1,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (686 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (852 hom.)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.981

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]

ENSG00000260729 (HGNC:):

ENSG00000261460 (HGNC:58304):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-72347801-G-C is Benign according to our data. Variant chr15-72347801-G-C is described in ClinVar as [Benign]. Clinvar id is 256349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1074-43C>G		intron_variant	Intron 9 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1107-43C>G		intron_variant	Intron 9 of 13		NP_001305754.1
HEXA	NR_134869.3	n.1115+247C>G		intron_variant	Intron 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1074-43C>G		intron_variant	Intron 9 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-1476C>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8559 AN: 152150 Hom.: 681 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0267 AC: 6709 AN: 250876 Hom.: 441 AF XY: 0.0202 AC XY: 2740 AN XY: 135610

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0967

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000871

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.00992 AC: 14097 AN: 1421450 Hom.: 852 Cov.: 25 AF XY: 0.00877 AC XY: 6225 AN XY: 709938

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.0942

Gnomad4 ASJ exome AF: 0.00158

Gnomad4 EAS exome AF: 0.000506

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0564 AC: 8594 AN: 152268 Hom.: 686 Cov.: 32 AF XY: 0.0554 AC XY: 4124 AN XY: 74460

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.0710

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.0526

Alfa AF: 0.00801 Hom.: 13

Bravo AF: 0.0680

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 03, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tay-Sachs disease Benign:1

Apr 12, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs16956759; hg19: chr15-72640142;