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GeneBe

3-50295046-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003549.4(HYAL3):c.557G>T(p.Arg186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,613,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

HYAL3
NM_003549.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.03
Variant links:
Genes affected
HYAL3 (HGNC:5322): (hyaluronidase 3) This gene encodes a member of the hyaluronidase family. Hyaluronidases are endoglycosidase enzymes that degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. The regulated turnover of hyaluronan plays a critical role in many biological processes including cell proliferation, migration and differentiation. The encoded protein may also play an important role in sperm function. This gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression, and the expression of specific transcript variants may be indicative of tumor status. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and some isoforms may lack hyaluronidase activity. This gene overlaps and is on the same strand as N-acetyltransferase 6 (GCN5-related), and some transcripts of each gene share a portion of the first exon. [provided by RefSeq, Jan 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.087757945).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HYAL3NM_003549.4 linkuse as main transcriptc.557G>T p.Arg186Leu missense_variant 2/4 ENST00000336307.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HYAL3ENST00000336307.6 linkuse as main transcriptc.557G>T p.Arg186Leu missense_variant 2/41 NM_003549.4 P1O43820-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000128
AC:
32
AN:
250570
Hom.:
0
AF XY:
0.0000738
AC XY:
10
AN XY:
135592
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000232
Gnomad NFE exome
AF:
0.000230
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000194
AC:
284
AN:
1461080
Hom.:
0
Cov.:
31
AF XY:
0.000176
AC XY:
128
AN XY:
726840
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:
0.00
Gnomad4 FIN exome
AF:
0.000265
Gnomad4 NFE exome
AF:
0.000230
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152228
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000150
Hom.:
0
Bravo
AF:
0.0000907
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 04, 2023The c.557G>T (p.R186L) alteration is located in exon 2 (coding exon 1) of the HYAL3 gene. This alteration results from a G to T substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a leucine (L). 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
0.086
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.58
Cadd
Benign
2.9
Dann
Benign
0.89
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.12
N
M_CAP
Benign
0.0084
T
MetaRNN
Benign
0.088
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;M;M;M
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-3.5
D;D;.;D
REVEL
Benign
0.026
Sift
Benign
0.44
T;T;.;T
Sift4G
Benign
0.14
T;T;T;T
Polyphen
0.60
P;P;P;P
Vest4
0.14
MVP
0.076
MPC
0.42
ClinPred
0.17
T
GERP RS
-0.66
Varity_R
0.19
gMVP
0.70

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: rs199964334; hg19: chr3-50332477; API