NM_003773.5:c.1132C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_003773.5(HYAL2):c.1132C>T(p.Arg378Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,880 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 9.70

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 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, 0.875

PP5

Variant 3-50318419-G-A is Pathogenic according to our data. Variant chr3-50318419-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1065395.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYAL2	NM_003773.5 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 4 of 4	ENST00000357750.9	NP_003764.3	Q12891
HYAL2	NM_033158.5 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 5 of 5		NP_149348.2	Q12891
HYAL2	XM_005265524.3 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 5 of 5		XP_005265581.1	Q12891
HYAL2	XM_005265525.3 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 4 of 4		XP_005265582.1	Q12891

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HYAL2	ENST00000357750.9 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 4 of 4	1	NM_003773.5	ENSP00000350387.4	Q12891
HYAL2	ENST00000395139.7 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 4 of 4	1		ENSP00000378571.3	Q12891
HYAL2	ENST00000447092.5 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 3 of 3	1		ENSP00000401853.1	Q12891
HYAL2	ENST00000442581.1 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 5 of 5	2		ENSP00000406657.1	Q12891

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250238

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460880

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HYAL2 deficiency

Pathogenic:2

Jun 20, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2021

New Leaf Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

From Fasham et al. 2021: At extremely low frequency in gnomAD databases. In trans with p.(Ala64Thr). Cosegregation with disease in multiple affected family members (≤1/16). In silico missense prediction tools support a deleterious effect on the gene or gene product. A strong consensus supporting a clinical diagnosis with a specific phenotype. -

MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME

Pathogenic:1

Jan 15, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;.;.;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Pathogenic

3.4

M;M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.9

D;D;D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.80

MutPred

0.65

Loss of catalytic residue at R378 (P = 0.01);Loss of catalytic residue at R378 (P = 0.01);Loss of catalytic residue at R378 (P = 0.01);Loss of catalytic residue at R378 (P = 0.01);

MVP

0.82

MPC

1.7

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.93

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