rs2912218

chr15-72345367-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.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, single submitter B:1
• Conservation: PhyloP100: -0.134

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=-0.88).
• BP6: Variant 15-72345367-T-C is Benign according to our data. Variant chr15-72345367-T-C is described in ClinVar as [Benign]. Clinvar id is 673944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1526+79A>G		intron_variant		ENST00000268097.10
HEXA	NM_001318825.2	c.1559+79A>G		intron_variant
HEXA	NR_134869.3	n.1390A>G		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1526+79A>G		intron_variant		1	NM_000520.6	P1
	ENST00000570175.1	n.166-19T>C		intron_variant, non_coding_transcript_variant		1

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

Gnomad4 AFR exome AF: 0.0621

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.00186

Gnomad4 NFE exome AF: 0.000636

Gnomad4 OTH exome AF: 0.00487

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

Gnomad4 AFR AF: 0.0583

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0132 Hom.: 6

Bravo AF: 0.0191

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.79
Dann	Benign	0.61

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: rs2912218; hg19: chr15-72637708;