rs104893743
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_033159.4(HYAL1):c.802G>A(p.Glu268Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,614,166 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )
Consequence
HYAL1
NM_033159.4 missense
NM_033159.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 7.37
Genes affected
HYAL1 (HGNC:5320): (hyaluronidase 1) This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. This enzyme is active at an acidic pH and is the major hyaluronidase in plasma. Mutations in this gene are associated with mucopolysaccharidosis type IX, or hyaluronidase deficiency. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.983
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HYAL1 | NM_033159.4 | c.802G>A | p.Glu268Lys | missense_variant | 2/4 | ENST00000395144.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HYAL1 | ENST00000395144.7 | c.802G>A | p.Glu268Lys | missense_variant | 2/4 | 1 | NM_033159.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251402Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135902
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GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29AN XY: 727240
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74470
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of hyaluronoglucosaminidase Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2021 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 268 of the HYAL1 protein (p.Glu268Lys). This variant is present in population databases (rs104893743, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IX (PMID: 10339581). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3530). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 25, 1999 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 15, 2018 | The HYAL1 c.802G>A (p.Glu268Lys) variant is a missense variant that has been reported in one study in which it is found in a compound heterozygous state with a stop-gained variant in one individual with mucopolysaccharidosis IX (Triggs-Raine et al., 1999; Natowicz et al., 1996). The patient's unaffected father and paternal grandmother both carried the variant in a heterozygous state. The variant was not found in 100 control alleles and is reported at a frequency of 0.000256 in the European (non-Finnish) population of the Exome Aggregation Consortium. The patient had deficient serum hyaluronidase activity and 38- to 90-fold elevated concentration of serum hyaluronic acid (Natowicz et al., 1996). Triggs-Raine et al. (1999) predict the variant to disrupt HYAL1 activity because of the difference in charges between the glutamine and lysine residues. The Glu268 residue is highly conserved and is likely critical for the function of an active site in the HYAL1 protein. In silico analysis of native and mutant HYAL demonstrated differences in folding pattern, secondary structure elements, dihedral angles, and binding strength (Paul & Rajasekaran 2017). The evidence for this variant is limited. The p.Glu268Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type IX. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H;H;H;.;.
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);.;.;
MVP
MPC
0.84
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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