Genetic Variant HEXA:c.*257G>A (chr15-72343820-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is . The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000520.6(HEXA):c.*257G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000341 in 292,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HEXA
NM_000520.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.622

Publications

0 publications found

Variant links:

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: G2P, Genomics England PanelApp, ClinGen, Myriad Women's Health, PanelApp Australia, Labcorp Genetics (formerly Invitae)

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

CELF6-AS1 (HGNC:58304):

CELF6-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000520.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.*257G>A		3_prime_UTR	Exon 14 of 14	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.*257G>A		3_prime_UTR	Exon 14 of 14	NP_001305754.1	H3BP20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HEXA	ENST00000268097.10	TSL:1 MANE Select	c.*257G>A	3_prime_UTR	Exon 14 of 14	ENSP00000268097.6	P06865-1
ENSG00000260729	ENST00000379915.4	TSL:2	n.608+1626G>A	intron	N/A	ENSP00000478716.1	A0A087WUJ7
CELF6-AS1	ENST00000570175.1	TSL:1	n.166-1566C>T	intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000341

AC:

AN:

292926

Hom.:

Cov.:

AF XY:

0.00000633

AC XY:

AN XY:

157978

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8248

American (AMR)

AF:

0.00

AC:

AN:

13878

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8230

East Asian (EAS)

AF:

0.00

AC:

AN:

16560

South Asian (SAS)

AF:

0.00

AC:

AN:

43378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1196

European-Non Finnish (NFE)

AF:

0.00000585

AC:

AN:

170904

Other (OTH)

AF:

0.00

AC:

AN:

15736

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.9

(source)

DANN

Benign

0.62

PhyloP100

-0.62

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over