3-50318299-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003773.5(HYAL2):c.1252A>C(p.Ile418Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,613,504 control chromosomes in the GnomAD database, including 13,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 2295 hom., cov: 32)

Exomes 𝑓: 0.037 ( 10760 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.344

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

orofacial cleft
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

HYAL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2889481E-5).

BP6

Variant 3-50318299-T-G is Benign according to our data. Variant chr3-50318299-T-G is described in ClinVar as Benign. ClinVar VariationId is 1229880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HYAL2	NM_003773.5 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 4 of 4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 5 of 5		NP_149348.2
HYAL2	XM_005265524.3 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 5 of 5		XP_005265581.1
HYAL2	XM_005265525.3 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 4 of 4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HYAL2	ENST00000357750.9 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 4 of 4	1	NM_003773.5	ENSP00000350387.4
HYAL2	ENST00000395139.7 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 4 of 4	1		ENSP00000378571.3
HYAL2	ENST00000447092.5 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 3 of 3	1		ENSP00000401853.1
HYAL2	ENST00000442581.1 link	c.1252A>C	p.Ile418Leu	missense_variant	Exon 5 of 5	2		ENSP00000406657.1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15854

AN:

152196

Hom.:

2293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.599

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0468

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.0876

GnomAD2 exomes

AF:

0.121

AC:

30469

AN:

250792

AF XY:

0.0988

show subpopulations

Gnomad AFR exome

AF:

0.179

Gnomad AMR exome

AF:

0.411

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.613

Gnomad FIN exome

AF:

0.0446

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.0677

GnomAD4 exome

AF:

0.0369

AC:

53907

AN:

1461190

Hom.:

10760

Cov.:

AF XY:

0.0334

AC XY:

24282

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.196

AC:

6550

AN:

33480

American (AMR)

AF:

0.389

AC:

17404

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00421

AC:

110

AN:

26132

East Asian (EAS)

AF:

0.535

AC:

21226

AN:

39700

South Asian (SAS)

AF:

0.0102

AC:

883

AN:

86258

European-Finnish (FIN)

AF:

0.0441

AC:

2324

AN:

52748

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00174

AC:

1938

AN:

1111996

Other (OTH)

AF:

0.0568

AC:

3430

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

2158

4316

6474

8632

10790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

710

1420

2130

2840

3550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.104

AC:

15882

AN:

152314

Hom.:

2295

Cov.:

AF XY:

0.111

AC XY:

8253

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.184

AC:

7653

AN:

41552

American (AMR)

AF:

0.267

AC:

4080

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.599

AC:

3100

AN:

5176

South Asian (SAS)

AF:

0.0209

AC:

101

AN:

4834

European-Finnish (FIN)

AF:

0.0468

AC:

498

AN:

10632

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00362

AC:

246

AN:

68024

Other (OTH)

AF:

0.0881

AC:

186

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

615

1230

1846

2461

3076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0428

Hom.:

1356

Bravo

AF:

0.130

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.107

AC:

12961

Asia WGS

AF:

0.204

AC:

709

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.21

T;T;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.0

.;.;.;T

MetaRNN

Benign

0.000013

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.1

N;N;N;N

PhyloP100

0.34

PrimateAI

Benign

0.31

PROVEAN

Benign

0.090

N;N;N;N

REVEL

Benign

0.096

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.87

T;T;T;T

Vest4

0.034

ClinPred

0.0018

GERP RS

5.2

Varity_R

0.062

gMVP

0.52

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over