3-50318427-C-T

Position:

chr3-50318427-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003773.5(HYAL2):c.1124G>A(p.Arg375His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,126 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: 0.0000062 ( 0 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL2	NM_003773.5 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	4/4	ENST00000357750.9	NP_003764.3	Q12891
HYAL2	NM_033158.5 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	5/5		NP_149348.2	Q12891
HYAL2	XM_005265524.3 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	5/5		XP_005265581.1	Q12891
HYAL2	XM_005265525.3 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	4/4		XP_005265582.1	Q12891

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HYAL2	ENST00000357750.9 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	4/4	1	NM_003773.5	ENSP00000350387.4	Q12891
HYAL2	ENST00000395139.7 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	4/4	1		ENSP00000378571.3	Q12891
HYAL2	ENST00000447092.5 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	3/3	1		ENSP00000401853.1	Q12891
HYAL2	ENST00000442581.1 linkuse as main transcript	c.1124G>A	p.Arg375His	missense_variant	5/5	2		ENSP00000406657.1	Q12891

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250070

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135614

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460860

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726758

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Sep 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;D;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;.;.;D

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.4

M;M;M;M

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.74

MutPred

0.53

Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);

MVP

0.88

MPC

1.6

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.88

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