rs16956759

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-72347801-G-C
• chr15-72347801-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

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:):

CELF6-AS1 (HGNC:58304):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-72347801-G-C is Benign according to our data. Variant chr15-72347801-G-C is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. 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.1074-43C>G		intron	N/A	NP_000511.2
	HEXA	NM_001318825.2		c.1107-43C>G		intron	N/A	NP_001305754.1
	HEXA	NR_134869.3		n.1115+247C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1074-43C>G		intron	N/A	ENSP00000268097.6
	HEXA	ENST00000567159.5	TSL:1	c.1074-43C>G		intron	N/A	ENSP00000456489.1
	ENSG00000260729	ENST00000379915.4	TSL:2	n.413-1476C>G		intron	N/A	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

GnomAD2 exomes AF: 0.0267 AC: 6709 AN: 250876 AF XY: 0.0202

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 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

African (AFR) AF: 0.182 AC: 5942 AN: 32708

American (AMR) AF: 0.0942 AC: 4202 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 41 AN: 25876

East Asian (EAS) AF: 0.000506 AC: 20 AN: 39500

South Asian (SAS) AF: 0.00320 AC: 273 AN: 85432

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53408

Middle Eastern (MID) AF: 0.0142 AC: 81 AN: 5704

European-Non Finnish (NFE) AF: 0.00236 AC: 2541 AN: 1075196

Other (OTH) AF: 0.0167 AC: 985 AN: 59014

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

African (AFR) AF: 0.173 AC: 7197 AN: 41516

American (AMR) AF: 0.0710 AC: 1087 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68026

Other (OTH) AF: 0.0526 AC: 111 AN: 2112

Alfa AF: 0.00801 Hom.: 13

Bravo AF: 0.0680

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Tay-Sachs disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs16956759; hg19: chr15-72640142;