rs117160567

Variant names:

• chr15-72351103-A-C
• rs117160567
• NM_000520.6:c.672+30T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001318825.2(HEXA):​c.705+30T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,390,626 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 32)
  • Exomes 𝑓: 0.024 (438 hom.)
• Consequence: HEXA NM_001318825.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: -0.261
• 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=-0.84).
• BP6: Variant 15-72351103-A-C is Benign according to our data. Variant chr15-72351103-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.016 (2435/152290) while in subpopulation SAS AF = 0.0494 (238/4822). AF 95% confidence interval is 0.0442. There are 40 homozygotes in GnomAd4. There are 1172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318825.2. 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.672+30T>G		intron	N/A	NP_000511.2
	HEXA	NM_001318825.2		c.705+30T>G		intron	N/A	NP_001305754.1
	HEXA	NR_134869.3		n.714+30T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.672+30T>G		intron	N/A	ENSP00000268097.6
	HEXA	ENST00000567159.5	TSL:1	c.672+30T>G		intron	N/A	ENSP00000456489.1
	CELF6-AS1	ENST00000570175.1	TSL:1	n.2457A>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2433 AN: 152172 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0191 AC: 4791 AN: 250938 AF XY: 0.0217

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.00692

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00814

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0236 AC: 29195 AN: 1238336 Hom.: 438 Cov.: 18 AF XY: 0.0247 AC XY: 15493 AN XY: 627650

African (AFR) AF: 0.00415 AC: 120 AN: 28942

American (AMR) AF: 0.00743 AC: 330 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 497 AN: 24782

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38716

South Asian (SAS) AF: 0.0467 AC: 3815 AN: 81700

European-Finnish (FIN) AF: 0.00930 AC: 496 AN: 53320

Middle Eastern (MID) AF: 0.0197 AC: 106 AN: 5382

European-Non Finnish (NFE) AF: 0.0251 AC: 22759 AN: 908026

Other (OTH) AF: 0.0201 AC: 1066 AN: 53030

GnomAD4 genome AF: 0.0160 AC: 2435 AN: 152290 Hom.: 40 Cov.: 32 AF XY: 0.0157 AC XY: 1172 AN XY: 74478

African (AFR) AF: 0.00476 AC: 198 AN: 41568

American (AMR) AF: 0.0115 AC: 176 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0494 AC: 238 AN: 4822

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1633 AN: 68020

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0206 Hom.: 103

Bravo AF: 0.0150

Asia WGS AF: 0.0260 AC: 92 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117160567; hg19: chr15-72643444;