rs199914308

Variant names:

• chr15-72344146-A-G
• rs199914308
• NM_000520.6:c.1527-6T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000520.6(HEXA):​c.1527-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,276 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (5 hom.)
• Consequence: HEXA NM_000520.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001057
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.52
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-72344146-A-G is Benign according to our data. Variant chr15-72344146-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194339.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.1527-6T>C		splice_region intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1560-6T>C		splice_region intron	N/A	NP_001305754.1	H3BP20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1527-6T>C		splice_region intron	N/A	ENSP00000268097.6	P06865-1
	ENSG00000260729	ENST00000379915.4	TSL:2	n.608+1300T>C		intron	N/A	ENSP00000478716.1	A0A087WUJ7
	CELF6-AS1	ENST00000570175.1	TSL:1	n.166-1240A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00123 AC: 310 AN: 251334 AF XY: 0.00116

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000680 AC: 993 AN: 1460958 Hom.: 5 Cov.: 30 AF XY: 0.000671 AC XY: 488 AN XY: 726830

African (AFR) AF: 0.000688 AC: 23 AN: 33452

American (AMR) AF: 0.00143 AC: 64 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 354 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5766

European-Non Finnish (NFE) AF: 0.000373 AC: 414 AN: 1111270

Other (OTH) AF: 0.00196 AC: 118 AN: 60348

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74482

African (AFR) AF: 0.000650 AC: 27 AN: 41566

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	3	Tay-Sachs disease (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.16		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: rs199914308; hg19: chr15-72636487;