ENST00000570175.1:n.1151C>T

Variant names:

• chr15-72346371-C-T
• rs2303448
• NM_000520.6:c.1331-46G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000570175.1(CELF6-AS1):​n.1151C>T 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 0.0604 in 1,552,948 control chromosomes in the GnomAD database, including 3,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (224 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3025 hom.)
• Consequence: CELF6-AS1 ENST00000570175.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.50
• Publications: 5 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: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

CELF6-AS1 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-72346371-C-T is Benign according to our data. Variant chr15-72346371-C-T is described in ClinVar as Benign. ClinVar VariationId is 256350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000570175.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.1331-46G>A		intron	N/A	NP_000511.2
	HEXA	NM_001318825.2		c.1364-46G>A		intron	N/A	NP_001305754.1
	HEXA	NR_134869.3		n.1116-46G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1331-46G>A		intron	N/A	ENSP00000268097.6
	HEXA	ENST00000567159.5	TSL:1	c.1331-46G>A		intron	N/A	ENSP00000456489.1
	CELF6-AS1	ENST00000570175.1	TSL:1	n.1151C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6951 AN: 152120 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0552 AC: 13624 AN: 246764 AF XY: 0.0575

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0634

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0619 AC: 86774 AN: 1400710 Hom.: 3025 Cov.: 22 AF XY: 0.0627 AC XY: 43934 AN XY: 700494

African (AFR) AF: 0.00918 AC: 297 AN: 32354

American (AMR) AF: 0.0292 AC: 1297 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 430 AN: 25692

East Asian (EAS) AF: 0.145 AC: 5727 AN: 39384

South Asian (SAS) AF: 0.0664 AC: 5638 AN: 84848

European-Finnish (FIN) AF: 0.0435 AC: 2320 AN: 53308

Middle Eastern (MID) AF: 0.0649 AC: 367 AN: 5656

European-Non Finnish (NFE) AF: 0.0640 AC: 67581 AN: 1056732

Other (OTH) AF: 0.0534 AC: 3117 AN: 58318

GnomAD4 genome AF: 0.0456 AC: 6947 AN: 152238 Hom.: 224 Cov.: 32 AF XY: 0.0447 AC XY: 3325 AN XY: 74430

African (AFR) AF: 0.0111 AC: 461 AN: 41538

American (AMR) AF: 0.0286 AC: 437 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.117 AC: 607 AN: 5176

South Asian (SAS) AF: 0.0630 AC: 304 AN: 4826

European-Finnish (FIN) AF: 0.0433 AC: 460 AN: 10616

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0640 AC: 4349 AN: 68002

Other (OTH) AF: 0.0417 AC: 88 AN: 2112

Alfa AF: 0.0573 Hom.: 166

Bravo AF: 0.0428

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.72
DANN	Benign	0.61
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2303448; hg19: chr15-72638712; COSMIC: COSV107268213; COSMIC: COSV107268213;