chr3-50320438-A-C

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.52T>G(p.Ser18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,585,186 control chromosomes in the GnomAD database, including 344,347 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 40928 hom., cov: 35)

Exomes 𝑓: 0.65 ( 303419 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00700

Publications

43 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 links:

TUSC2 (HGNC:17034): (tumor suppressor 2, mitochondrial calcium regulator) Predicted to be involved in inflammatory response and regulation of mitochondrial membrane potential. Predicted to act upstream of or within several processes, including natural killer cell differentiation; neutrophil-mediated killing of gram-negative bacterium; and regulation of cytokine production. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

TUSC2 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=6.116206E-7).

BP6

Variant 3-50320438-A-C is Benign according to our data. Variant chr3-50320438-A-C is described in ClinVar as Benign. ClinVar VariationId is 1183695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYAL2	NM_003773.5 link	c.52T>G	p.Ser18Ala	missense_variant	Exon 2 of 4	ENST00000357750.9	NP_003764.3	Q12891
HYAL2	NM_033158.5 link	c.52T>G	p.Ser18Ala	missense_variant	Exon 3 of 5		NP_149348.2	Q12891
HYAL2	XM_005265524.3 link	c.52T>G	p.Ser18Ala	missense_variant	Exon 3 of 5		XP_005265581.1	Q12891
HYAL2	XM_005265525.3 link	c.52T>G	p.Ser18Ala	missense_variant	Exon 2 of 4		XP_005265582.1	Q12891

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9 link	c.52T>G	p.Ser18Ala	missense_variant	Exon 2 of 4	1	NM_003773.5	ENSP00000350387.4		Q12891

Frequencies

GnomAD3 genomes

AF:

0.722

AC:

109799

AN:

152168

Hom.:

40867

Cov.:

show subpopulations

Gnomad AFR

AF:

0.888

Gnomad AMI

AF:

0.676

Gnomad AMR

AF:

0.808

Gnomad ASJ

AF:

0.647

Gnomad EAS

AF:

0.774

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.626

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.637

Gnomad OTH

AF:

0.734

GnomAD2 exomes

AF:

0.676

AC:

152703

AN:

225886

AF XY:

0.654

show subpopulations

Gnomad AFR exome

AF:

0.894

Gnomad AMR exome

AF:

0.850

Gnomad ASJ exome

AF:

0.648

Gnomad EAS exome

AF:

0.771

Gnomad FIN exome

AF:

0.627

Gnomad NFE exome

AF:

0.646

Gnomad OTH exome

AF:

0.660

GnomAD4 exome

AF:

0.646

AC:

925309

AN:

1432900

Hom.:

303419

Cov.:

AF XY:

0.638

AC XY:

452717

AN XY:

709376

show subpopulations

African (AFR)

AF:

0.900

AC:

29779

AN:

33080

American (AMR)

AF:

0.841

AC:

36035

AN:

42832

Ashkenazi Jewish (ASJ)

AF:

0.647

AC:

15582

AN:

24086

East Asian (EAS)

AF:

0.793

AC:

31224

AN:

39390

South Asian (SAS)

AF:

0.424

AC:

34641

AN:

81712

European-Finnish (FIN)

AF:

0.627

AC:

32066

AN:

51182

Middle Eastern (MID)

AF:

0.626

AC:

3489

AN:

5570

European-Non Finnish (NFE)

AF:

0.642

AC:

703458

AN:

1095990

Other (OTH)

AF:

0.661

AC:

39035

AN:

59058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

20361

40722

61084

81445

101806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18818

37636

56454

75272

94090

<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:

0.722

AC:

109920

AN:

152286

Hom.:

40928

Cov.:

AF XY:

0.716

AC XY:

53306

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.888

AC:

36934

AN:

41586

American (AMR)

AF:

0.808

AC:

12371

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.647

AC:

2248

AN:

3472

East Asian (EAS)

AF:

0.773

AC:

3993

AN:

5164

South Asian (SAS)

AF:

0.416

AC:

2008

AN:

4826

European-Finnish (FIN)

AF:

0.626

AC:

6638

AN:

10606

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.637

AC:

43350

AN:

68006

Other (OTH)

AF:

0.737

AC:

1560

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

1590

3180

4769

6359

7949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<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:

0.675

Hom.:

34863

Bravo

AF:

0.752

TwinsUK

AF:

0.652

AC:

2416

ALSPAC

AF:

0.646

AC:

2488

ESP6500AA

AF:

0.883

AC:

3883

ESP6500EA

AF:

0.644

AC:

5541

ExAC

AF:

0.656

AC:

79203

Asia WGS

AF:

0.581

AC:

2024

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

0.053

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.20

T;T;T;T;.;.;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.031

.;.;.;T;T;T;T;T;T

MetaRNN

Benign

6.1e-7

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.99

N;N;N;N;.;.;.;.;.

PhyloP100

0.0070

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.27

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.068

Sift

Benign

1.0

T;T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;.;.;.;.

Polyphen

0.0

B;B;B;B;.;.;.;.;.

Vest4

0.019

MPC

0.41

ClinPred

0.00087

GERP RS

3.7

Varity_R

0.049

gMVP

0.27

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