Genetic Variant HEXA:p.Val253Val (chr15-72350564-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000520.6(HEXA):c.759G>A(p.Val253Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,614,144 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 26 hom. )

Consequence

HEXA
NM_000520.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.293

Publications

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

HEXA links:

CELF6-AS1 (HGNC:58304):

CELF6-AS1 links:

ENSG00000260729 (HGNC:):

ENSG00000260729 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: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 15-72350564-C-T is Benign according to our data. Variant chr15-72350564-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.293 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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.759G>A	p.Val253Val	synonymous	Exon 7 of 14	NP_000511.2	P06865-1
HEXA	NM_001318825.2		c.792G>A	p.Val264Val	synonymous	Exon 7 of 14	NP_001305754.1	H3BP20
HEXA	NR_134869.3		n.801G>A		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXA	ENST00000268097.10	TSL:1 MANE Select	c.759G>A	p.Val253Val	synonymous	Exon 7 of 14	ENSP00000268097.6	P06865-1
HEXA	ENST00000567159.5	TSL:1	c.759G>A	p.Val253Val	synonymous	Exon 7 of 13	ENSP00000456489.1	H3BS10
CELF6-AS1	ENST00000570175.1	TSL:1	n.1918C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00407

AC:

620

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00628

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00458

AC:

1151

AN:

251480

AF XY:

0.00485

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00446

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00698

Gnomad NFE exome

AF:

0.00665

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00508

AC:

7423

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

3732

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33476

American (AMR)

AF:

0.00221

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00402

AC:

105

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00210

AC:

181

AN:

86254

European-Finnish (FIN)

AF:

0.00614

AC:

328

AN:

53414

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00574

AC:

6380

AN:

1111988

Other (OTH)

AF:

0.00432

AC:

261

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

384

768

1153

1537

1921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<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:

0.00407

AC:

620

AN:

152318

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41558

American (AMR)

AF:

0.00457

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00628

AC:

427

AN:

68036

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00555

Hom.:

Bravo

AF:

0.00389

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00711

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Tay-Sachs disease (3)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over