rs57733983

Variant names:

• chr15-72346050-T-C
• rs57733983
• NM_000520.6:c.1421+185A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-72346050-T-C
• chr15-72346050-T-G

Variant summary

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

The NM_000520.6(HEXA):​c.1421+185A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 630,202 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (34 hom.)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-72346050-T-C is Benign according to our data. Variant chr15-72346050-T-C is described in ClinVar as Benign. ClinVar VariationId is 1252412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

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.1421+185A>G		intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1454+185A>G		intron	N/A	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1206+185A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1421+185A>G		intron	N/A	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.1421+185A>G		intron	N/A	ENSP00000456489.1	H3BS10
	CELF6-AS1	ENST00000570175.1	TSL:1	n.830T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2893 AN: 152136 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00652 AC: 3118 AN: 477948 Hom.: 34 Cov.: 4 AF XY: 0.00605 AC XY: 1529 AN XY: 252880

African (AFR) AF: 0.0515 AC: 672 AN: 13060

American (AMR) AF: 0.00613 AC: 141 AN: 22992

Ashkenazi Jewish (ASJ) AF: 0.0000686 AC: 1 AN: 14568

East Asian (EAS) AF: 0.00 AC: 0 AN: 31182

South Asian (SAS) AF: 0.000145 AC: 7 AN: 48144

European-Finnish (FIN) AF: 0.00197 AC: 82 AN: 41716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2018

European-Non Finnish (NFE) AF: 0.00715 AC: 1984 AN: 277526

Other (OTH) AF: 0.00864 AC: 231 AN: 26742

GnomAD4 genome AF: 0.0190 AC: 2897 AN: 152254 Hom.: 63 Cov.: 32 AF XY: 0.0179 AC XY: 1335 AN XY: 74454

African (AFR) AF: 0.0531 AC: 2206 AN: 41536

American (AMR) AF: 0.0101 AC: 154 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 68016

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.0137 Hom.: 8

Bravo AF: 0.0210

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.26
DANN	Benign	0.40
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs57733983; hg19: chr15-72638391;