rs1800428

Variant names:

• chr15-72375964-G-A
• rs1800428
• NM_000520.6:c.9C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000520.6(HEXA):​c.9C>T​(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,613,708 control chromosomes in the GnomAD database, including 1,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (131 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1702 hom.)
• Consequence: HEXA NM_000520.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.521
• Publications: 15 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]

ENSG00000260729 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-72375964-G-A is Benign according to our data. Variant chr15-72375964-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.521 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 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.9C>T	p.Ser3Ser	synonymous	Exon 1 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 14	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.51C>T		non_coding_transcript_exon	Exon 1 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 14	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 13	ENSP00000456489.1	H3BS10
	ENSG00000260729	ENST00000379915.4	TSL:2	n.9C>T		non_coding_transcript_exon	Exon 1 of 16	ENSP00000478716.1	A0A087WUJ7

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5011 AN: 152202 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0510

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0441

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0415 AC: 10372 AN: 250098 AF XY: 0.0427

Gnomad AFR exome AF: 0.00791

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0431

Gnomad OTH exome AF: 0.0395

GnomAD4 exome AF: 0.0433 AC: 63351 AN: 1461388 Hom.: 1702 Cov.: 31 AF XY: 0.0438 AC XY: 31878 AN XY: 727000

African (AFR) AF: 0.00618 AC: 207 AN: 33480

American (AMR) AF: 0.0263 AC: 1175 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 450 AN: 26132

East Asian (EAS) AF: 0.139 AC: 5529 AN: 39700

South Asian (SAS) AF: 0.0467 AC: 4024 AN: 86256

European-Finnish (FIN) AF: 0.0241 AC: 1277 AN: 52972

Middle Eastern (MID) AF: 0.0409 AC: 235 AN: 5740

European-Non Finnish (NFE) AF: 0.0432 AC: 48067 AN: 1111996

Other (OTH) AF: 0.0395 AC: 2387 AN: 60390

GnomAD4 genome AF: 0.0329 AC: 5007 AN: 152320 Hom.: 131 Cov.: 32 AF XY: 0.0325 AC XY: 2420 AN XY: 74482

African (AFR) AF: 0.00786 AC: 327 AN: 41590

American (AMR) AF: 0.0251 AC: 385 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.114 AC: 590 AN: 5164

South Asian (SAS) AF: 0.0508 AC: 245 AN: 4824

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0441 AC: 2999 AN: 68018

Other (OTH) AF: 0.0317 AC: 67 AN: 2116

Alfa AF: 0.0381 Hom.: 88

Bravo AF: 0.0317

Asia WGS AF: 0.0680 AC: 236 AN: 3478

EpiCase AF: 0.0433

EpiControl AF: 0.0453

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Tay-Sachs disease (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.93
PhyloP100		0.52
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=296/4	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: rs1800428; hg19: chr15-72668305; COSMIC: COSV51505476; COSMIC: COSV51505476;