chr3-50320213-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_003773.5(HYAL2):​c.277G>A​(p.Gly93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.675
Variant links:
Genes affected
HYAL2 (HGNC:5321): (hyaluronidase 2) This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[provided by RefSeq, Mar 2010]
TUSC2 (HGNC:17034): (tumor suppressor 2, mitochondrial calcium regulator) Predicted to be involved in inflammatory response and regulation of mitochondrial membrane potential. Predicted to act upstream of or within several processes, including natural killer cell differentiation; neutrophil-mediated killing of gram-negative bacterium; and regulation of cytokine production. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a disulfide_bond (size 293) in uniprot entity HYAL2_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_003773.5
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HYAL2NM_003773.5 linkc.277G>A p.Gly93Arg missense_variant Exon 2 of 4 ENST00000357750.9 NP_003764.3 Q12891
HYAL2NM_033158.5 linkc.277G>A p.Gly93Arg missense_variant Exon 3 of 5 NP_149348.2 Q12891
HYAL2XM_005265524.3 linkc.277G>A p.Gly93Arg missense_variant Exon 3 of 5 XP_005265581.1 Q12891
HYAL2XM_005265525.3 linkc.277G>A p.Gly93Arg missense_variant Exon 2 of 4 XP_005265582.1 Q12891

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HYAL2ENST00000357750.9 linkc.277G>A p.Gly93Arg missense_variant Exon 2 of 4 1 NM_003773.5 ENSP00000350387.4 Q12891

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461602
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 14, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.277G>A (p.G93R) alteration is located in exon 3 (coding exon 1) of the HYAL2 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the glycine (G) at amino acid position 93 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D;D;D;D;.;.
Eigen
Benign
0.021
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.80
.;.;.;T;T;T
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.74
D;D;D;D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.9
M;M;M;M;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-4.7
D;D;D;D;D;D
REVEL
Benign
0.097
Sift
Benign
0.065
T;T;T;T;D;D
Sift4G
Uncertain
0.052
T;T;T;T;T;.
Polyphen
0.97
D;D;D;D;.;.
Vest4
0.095
MutPred
0.74
Loss of methylation at R94 (P = 0.0457);Loss of methylation at R94 (P = 0.0457);Loss of methylation at R94 (P = 0.0457);Loss of methylation at R94 (P = 0.0457);Loss of methylation at R94 (P = 0.0457);Loss of methylation at R94 (P = 0.0457);
MVP
0.68
MPC
0.64
ClinPred
0.92
D
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.16
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1411759105; hg19: chr3-50357644; COSMIC: COSV99222884; COSMIC: COSV99222884; API