rs2912218

Variant names:

• chr15-72345367-T-C
• rs2912218
• NM_000520.6:c.1526+79A>G

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.1526+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,591,562 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (73 hom.)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.134
• Publications: 1 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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

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=-0.88).
• BP6: Variant 15-72345367-T-C is Benign according to our data. Variant chr15-72345367-T-C is described in ClinVar as Benign. ClinVar VariationId is 673944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0563 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.1526+79A>G		intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1559+79A>G		intron	N/A	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1390A>G		non_coding_transcript_exon	Exon 11 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1526+79A>G		intron	N/A	ENSP00000268097.6	P06865-1
	ENSG00000260729	ENST00000379915.4	TSL:2	n.608+79A>G		intron	N/A	ENSP00000478716.1	A0A087WUJ7
	CELF6-AS1	ENST00000570175.1	TSL:1	n.166-19T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2602 AN: 152228 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.00237 AC: 3408 AN: 1439216 Hom.: 73 Cov.: 30 AF XY: 0.00215 AC XY: 1536 AN XY: 713964

African (AFR) AF: 0.0621 AC: 2062 AN: 33210

American (AMR) AF: 0.00479 AC: 197 AN: 41156

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25646

East Asian (EAS) AF: 0.00 AC: 0 AN: 39250

South Asian (SAS) AF: 0.000156 AC: 13 AN: 83512

European-Finnish (FIN) AF: 0.00186 AC: 92 AN: 49330

Middle Eastern (MID) AF: 0.00837 AC: 48 AN: 5734

European-Non Finnish (NFE) AF: 0.000636 AC: 701 AN: 1101618

Other (OTH) AF: 0.00487 AC: 291 AN: 59760

GnomAD4 genome AF: 0.0171 AC: 2610 AN: 152346 Hom.: 71 Cov.: 33 AF XY: 0.0167 AC XY: 1242 AN XY: 74502

African (AFR) AF: 0.0583 AC: 2423 AN: 41574

American (AMR) AF: 0.00588 AC: 90 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68032

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.0132 Hom.: 6

Bravo AF: 0.0191

Asia WGS AF: 0.00433 AC: 15 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	-0.88
CADD	Benign	0.79
DANN	Benign	0.61
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

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: rs2912218; hg19: chr15-72637708;