Genetic Variant NM_000520.6:c.1518A>G (chr15-72345454-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000520.6(HEXA):c.1518A>G(p.Glu506Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.979 in 1,614,144 control chromosomes in the GnomAD database, including 778,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 62364 hom., cov: 34)

Exomes 𝑓: 0.99 ( 716186 hom. )

Consequence

HEXA
NM_000520.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.293

Publications

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

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

CELF6-AS1 (HGNC:58304):

CELF6-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 15-72345454-T-C is Benign according to our data. Variant chr15-72345454-T-C is described in ClinVar as Benign. ClinVar VariationId is 93191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.293 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXA	NM_000520.6	MANE Select	c.1518A>G	p.Glu506Glu	synonymous	Exon 13 of 14	NP_000511.2	P06865-1
HEXA	NM_001318825.2		c.1551A>G	p.Glu517Glu	synonymous	Exon 13 of 14	NP_001305754.1	H3BP20
HEXA	NR_134869.3		n.1303A>G		non_coding_transcript_exon	Exon 11 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1518A>G	p.Glu506Glu	synonymous	Exon 13 of 14	ENSP00000268097.6	P06865-1
HEXA	ENST00000567159.5	TSL:1	c.1518A>G	p.Glu506Glu	synonymous	Exon 13 of 13	ENSP00000456489.1	H3BS10
ENSG00000260729	ENST00000379915.4	TSL:2	n.600A>G		non_coding_transcript_exon	Exon 5 of 16	ENSP00000478716.1	A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.889

AC:

135239

AN:

152172

Hom.:

62345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.613

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.962

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.978

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.921

GnomAD2 exomes

AF:

0.971

AC:

244012

AN:

251424

AF XY:

0.979

show subpopulations

Gnomad AFR exome

AF:

0.605

Gnomad AMR exome

AF:

0.981

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.998

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.988

GnomAD4 exome

AF:

0.988

AC:

1444272

AN:

1461854

Hom.:

716186

Cov.:

AF XY:

0.989

AC XY:

719550

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.600

AC:

20071

AN:

33476

American (AMR)

AF:

0.979

AC:

43774

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26129

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39700

AN:

39700

South Asian (SAS)

AF:

0.999

AC:

86164

AN:

86254

European-Finnish (FIN)

AF:

0.998

AC:

53301

AN:

53408

Middle Eastern (MID)

AF:

0.971

AC:

5600

AN:

5768

European-Non Finnish (NFE)

AF:

0.999

AC:

1110666

AN:

1112000

Other (OTH)

AF:

0.975

AC:

58867

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

779

1559

2338

3118

3897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21630

43260

64890

86520

108150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.889

AC:

135312

AN:

152290

Hom.:

62364

Cov.:

AF XY:

0.892

AC XY:

66419

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.613

AC:

25421

AN:

41500

American (AMR)

AF:

0.962

AC:

14724

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3471

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5187

AN:

5188

South Asian (SAS)

AF:

0.999

AC:

4827

AN:

4834

European-Finnish (FIN)

AF:

0.997

AC:

10599

AN:

10628

Middle Eastern (MID)

AF:

0.976

AC:

287

AN:

294

European-Non Finnish (NFE)

AF:

0.998

AC:

67935

AN:

68040

Other (OTH)

AF:

0.922

AC:

1949

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

568

1136

1704

2272

2840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.959

Hom.:

74215

Bravo

AF:

0.873

Asia WGS

AF:

0.977

AC:

3397

AN:

3478

EpiCase

AF:

0.998

EpiControl

AF:

0.997

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (5)

Tay-Sachs disease (5)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

-0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over