rs104893743

Positions:

• chr3-50302155-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• 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]

ACMG classification

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: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251402 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135902

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hyaluronoglucosaminidase Pathogenic:1 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D;D;D;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.
Vest4		0.94
MutPred		0.94		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		0.88
MPC		0.84
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.98

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

Other links and lift over

dbSNP: rs104893743; hg19: chr3-50339586; COSMIC: COSV56496979; COSMIC: COSV56496979;