chr15-72350578-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000520.6(HEXA):​c.745C>T​(p.Arg249Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications U:1B:1O:3

Conservation

PhyloP100: 2.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEXANM_000520.6 linkc.745C>T p.Arg249Trp missense_variant Exon 7 of 14 ENST00000268097.10 NP_000511.2 P06865-1A0A0S2Z3W3
HEXANM_001318825.2 linkc.778C>T p.Arg260Trp missense_variant Exon 7 of 14 NP_001305754.1 P06865H3BP20B4DVA7
HEXANR_134869.3 linkn.787C>T non_coding_transcript_exon_variant Exon 7 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEXAENST00000268097.10 linkc.745C>T p.Arg249Trp missense_variant Exon 7 of 14 1 NM_000520.6 ENSP00000268097.6 P06865-1
ENSG00000260729ENST00000379915.4 linkn.413-4253C>T intron_variant Intron 3 of 15 2 ENSP00000478716.1 A0A087WUJ7

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00135
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000191
AC:
48
AN:
251478
Hom.:
0
AF XY:
0.000199
AC XY:
27
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000707
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000290
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000282
AC:
412
AN:
1461828
Hom.:
0
Cov.:
31
AF XY:
0.000272
AC XY:
198
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000579
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000304
Gnomad4 OTH exome
AF:
0.000696
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152292
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00135
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000333
Hom.:
1
Bravo
AF:
0.000246
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000582
AC:
5
ExAC
AF:
0.000231
AC:
28
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000600
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity; other
Submissions summary: Uncertain:1Benign:1Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1Other:1
Jul 19, 2016
Eurofins Ntd Llc (ga)
Significance: other
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Aug 11, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The HEXA c.745C>T (p.Arg249Trp) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 28/121408 (1/4336), which does not exceed the estimated maximal expected allele frequency for a pathogenic HEXA variant of 1/715. The variant of interest is known to be a common pseudodeficiency allele, which is not associated with neurologic disease but is associated wtih reduced degradation of the synthetic substrate when HEX A enzymatic activity is determined (Gene Reviews). Therefore, the variant of interest is classified as Benign. -

Feb 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

HEXA: PM2:Supporting -

Tay-Sachs disease Other:2
May 30, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: other
Review Status: criteria provided, single submitter
Collection Method: clinical testing

pseudodeficiency The Arg249Trp variant in HEXA is a well-established pseudodeficiency allele for HEXA activity (Cao 1993) and has been identified in 0.05% (5/8594) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs138058578). The Arg249Trp variant is clinically benign (i.e., has normal activity in vivo) but has reduced HEXA enzyme activity toward synthetic substrates and therefore can produce a false positive result on enzyme analysis, a technique often used for carrier screening (Hoffman 2013).

Dec 13, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: other
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- pseudodeficiency allele

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;.;D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-7.8
D;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.88
MVP
1.0
MPC
0.73
ClinPred
0.95
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.92
gMVP
0.97

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138058578; hg19: chr15-72642919; COSMIC: COSV99173798; COSMIC: COSV99173798; API