15-72376198-T-C

Variant names:

• chr15-72376198-T-C
• rs4777505
• ENST00000567598.2:n.148T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NR_027262.1(HEXA-AS1):​n.86T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,428,282 control chromosomes in the GnomAD database, including 621,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (54665 hom., cov: 34)
  • Exomes 𝑓: 0.94 (566935 hom.)
• Consequence: HEXA-AS1 NR_027262.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.137

Genes affected

HEXA-AS1 (HGNC:25810): (HEXA antisense RNA 1)

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]

ENSG00000260729 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-72376198-T-C is Benign according to our data. Variant chr15-72376198-T-C is described in ClinVar as [Benign]. Clinvar id is 1264792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72376198-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA-AS1	NR_027262.1	n.86T>C		non_coding_transcript_exon_variant	Exon 1 of 1
HEXA	NM_000520.6	c.-226A>G		upstream_gene_variant		ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.-226A>G		upstream_gene_variant			NP_001305754.1
HEXA	NR_134869.3	n.-184A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.-226A>G		upstream_gene_variant		1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.-226A>G		upstream_gene_variant		2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 125112 AN: 152128 Hom.: 54658 Cov.: 34

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.981

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.952

Gnomad OTH AF: 0.856

GnomAD4 exome AF: 0.940 AC: 1199206 AN: 1276036 Hom.: 566935 Cov.: 57 AF XY: 0.941 AC XY: 582549 AN XY: 619186

Gnomad4 AFR exome AF: 0.478

Gnomad4 AMR exome AF: 0.933

Gnomad4 ASJ exome AF: 0.982

Gnomad4 EAS exome AF: 0.862

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.974

Gnomad4 NFE exome AF: 0.953

Gnomad4 OTH exome AF: 0.925

GnomAD4 genome AF: 0.822 AC: 125152 AN: 152246 Hom.: 54665 Cov.: 34 AF XY: 0.828 AC XY: 61656 AN XY: 74452

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.918

Gnomad4 ASJ AF: 0.981

Gnomad4 EAS AF: 0.885

Gnomad4 SAS AF: 0.947

Gnomad4 FIN AF: 0.976

Gnomad4 NFE AF: 0.952

Gnomad4 OTH AF: 0.857

Alfa AF: 0.927 Hom.: 62175

Bravo AF: 0.803

Asia WGS AF: 0.899 AC: 3126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.45

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: rs4777505; hg19: chr15-72668539;