rs117513345

Variant names:

• chr15-72350564-C-T
• rs117513345
• NM_000520.6:c.759G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000520.6(HEXA):​c.759G>A​(p.Val253Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,614,144 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (26 hom.)
• Consequence: HEXA NM_000520.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.293
• Publications: 2 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

CELF6-AS1 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 15-72350564-C-T is Benign according to our data. Variant chr15-72350564-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.293 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 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.759G>A	p.Val253Val	synonymous	Exon 7 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.792G>A	p.Val264Val	synonymous	Exon 7 of 14	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.801G>A		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.759G>A	p.Val253Val	synonymous	Exon 7 of 14	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.759G>A	p.Val253Val	synonymous	Exon 7 of 13	ENSP00000456489.1	H3BS10
	CELF6-AS1	ENST00000570175.1	TSL:1	n.1918C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 620 AN: 152200 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00458 AC: 1151 AN: 251480 AF XY: 0.00485

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.00665

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00508 AC: 7423 AN: 1461826 Hom.: 26 Cov.: 31 AF XY: 0.00513 AC XY: 3732 AN XY: 727208

African (AFR) AF: 0.000926 AC: 31 AN: 33476

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00210 AC: 181 AN: 86254

European-Finnish (FIN) AF: 0.00614 AC: 328 AN: 53414

Middle Eastern (MID) AF: 0.00644 AC: 37 AN: 5746

European-Non Finnish (NFE) AF: 0.00574 AC: 6380 AN: 1111988

Other (OTH) AF: 0.00432 AC: 261 AN: 60390

GnomAD4 genome AF: 0.00407 AC: 620 AN: 152318 Hom.: 5 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74484

African (AFR) AF: 0.000578 AC: 24 AN: 41558

American (AMR) AF: 0.00457 AC: 70 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00628 AC: 427 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00555 Hom.: 2

Bravo AF: 0.00389

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs117513345; hg19: chr15-72642905; COSMIC: COSV51507200; COSMIC: COSV51507200;