chr3-50319606-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_003773.5(HYAL2):c.884G>A(p.Arg295Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,312 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
HYAL2
NM_003773.5 missense
NM_003773.5 missense
Scores
3
8
7
Clinical Significance
Conservation
PhyloP100: 4.94
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a disulfide_bond (size 293) in uniprot entity HYAL2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003773.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.836
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HYAL2 | NM_003773.5 | c.884G>A | p.Arg295Gln | missense_variant | 2/4 | ENST00000357750.9 | |
HYAL2 | NM_033158.5 | c.884G>A | p.Arg295Gln | missense_variant | 3/5 | ||
HYAL2 | XM_005265524.3 | c.884G>A | p.Arg295Gln | missense_variant | 3/5 | ||
HYAL2 | XM_005265525.3 | c.884G>A | p.Arg295Gln | missense_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HYAL2 | ENST00000357750.9 | c.884G>A | p.Arg295Gln | missense_variant | 2/4 | 1 | NM_003773.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249642Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135330
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461032Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726784
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2023 | The c.884G>A (p.R295Q) 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 884, causing the arginine (R) at amino acid position 295 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;D;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Loss of methylation at R295 (P = 0.0547);Loss of methylation at R295 (P = 0.0547);Loss of methylation at R295 (P = 0.0547);Loss of methylation at R295 (P = 0.0547);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at