3-50319032-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_003773.5(HYAL2):c.935C>T(p.Ser312Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000243 in 1,605,574 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

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]

HYAL2 links:

Genome browser will be placed here

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, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HYAL2	NM_003773.5 linkuse as main transcript	c.935C>T	p.Ser312Phe	missense_variant	3/4	ENST00000357750.9
HYAL2	NM_033158.5 linkuse as main transcript	c.935C>T	p.Ser312Phe	missense_variant	4/5
HYAL2	XM_005265524.3 linkuse as main transcript	c.935C>T	p.Ser312Phe	missense_variant	4/5
HYAL2	XM_005265525.3 linkuse as main transcript	c.935C>T	p.Ser312Phe	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYAL2	ENST00000357750.9 linkuse as main transcript	c.935C>T	p.Ser312Phe	missense_variant	3/4	1	NM_003773.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

249796

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135042

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:

0.00

Gnomad NFE exome

AF:

0.0000798

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1453408

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

721448

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:

0.00

Gnomad4 NFE exome

AF:

0.0000307

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000971

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HYAL2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2024

The HYAL2 c.935C>T variant is predicted to result in the amino acid substitution p.Ser312Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.8

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Benign

0.070

T;T;T;T

Polyphen

0.97

D;D;D;D

Vest4

0.90

MutPred

0.52

Loss of glycosylation at S312 (P = 0.0203);Loss of glycosylation at S312 (P = 0.0203);Loss of glycosylation at S312 (P = 0.0203);Loss of glycosylation at S312 (P = 0.0203);

MVP

0.76

MPC

1.4

ClinPred

0.58

GERP RS

5.8

Varity_R

0.50

gMVP

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over