rs35949555

chr15-72343447-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000520.6(HEXA):c.*630A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 152,994 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (343 hom., cov: 31)
  • Exomes 𝑓: 0.029 (1 hom.)
• Consequence: HEXA NM_000520.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.176

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-72343447-T-C is Benign according to our data. Variant chr15-72343447-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 317032.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.*630A>G		3_prime_UTR_variant	14/14	ENST00000268097.10
HEXA	NM_001318825.2	c.*630A>G		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.*630A>G		3_prime_UTR_variant	14/14	1	NM_000520.6	P1
	ENST00000570175.1	n.166-1939T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8091 AN: 151862 Hom.: 345 Cov.: 31

Gnomad AFR AF: 0.0793

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.0517

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0503

GnomAD4 exome AF: 0.0286 AC: 29 AN: 1014 Hom.: 1 Cov.: 0 AF XY: 0.0230 AC XY: 12 AN XY: 522

Gnomad4 AMR exome AF: 0.0380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.375

Gnomad4 SAS exome AF: 0.0556

Gnomad4 NFE exome AF: 0.0216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0533 AC: 8096 AN: 151980 Hom.: 343 Cov.: 31 AF XY: 0.0534 AC XY: 3965 AN XY: 74258

Gnomad4 AFR AF: 0.0793

Gnomad4 AMR AF: 0.0284

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.0522

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0537 Hom.: 38

Bravo AF: 0.0530

Asia WGS AF: 0.118 AC: 408 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tay-Sachs disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.1
Dann	Benign	0.43

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: rs35949555; hg19: chr15-72635788;