rs7080536

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_004132.5(HABP2):c.1601G>A(p.Gly534Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,420 control chromosomes in the GnomAD database, including 1,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1069 hom. )

Consequence

HABP2
NM_004132.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:2

Conservation

PhyloP100: 9.29

Publications

102 publications found

Variant links:

Genes affected

HABP2 (HGNC:4798): (hyaluronan binding protein 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by hepatocytes and proteolytically processed to generate heavy and light chains that form the mature heterodimer. Further autoproteolysis leads to smaller, inactive peptides. This extracellular protease binds hyaluronic acid and may play a role in the coagulation and fibrinolysis systems. Mutations in this gene are associated with nonmedullary thyroid cancer and susceptibility to venous thromboembolism. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

HABP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.009163111).

BP6

Variant 10-113588287-G-A is Benign according to our data. Variant chr10-113588287-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5974.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.023 (3503/152236) while in subpopulation NFE AF = 0.0375 (2549/67994). AF 95% confidence interval is 0.0363. There are 54 homozygotes in GnomAd4. There are 1671 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3503 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HABP2	NM_004132.5 link	c.1601G>A	p.Gly534Glu	missense_variant	Exon 13 of 13	ENST00000351270.4	NP_004123.1	Q14520-1
HABP2	NM_001177660.3 link	c.1523G>A	p.Gly508Glu	missense_variant	Exon 13 of 13		NP_001171131.1	Q14520-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HABP2	ENST00000351270.4 link	c.1601G>A	p.Gly534Glu	missense_variant	Exon 13 of 13	1	NM_004132.5	ENSP00000277903.4		Q14520-1
HABP2	ENST00000542051.5 link	c.1523G>A	p.Gly508Glu	missense_variant	Exon 13 of 13	2		ENSP00000443283.1		Q14520-2

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3501

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00662

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0223

AC:

5608

AN:

251244

AF XY:

0.0231

show subpopulations

Gnomad AFR exome

AF:

0.00584

Gnomad AMR exome

AF:

0.00773

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0268

Gnomad NFE exome

AF:

0.0364

Gnomad OTH exome

AF:

0.0242

GnomAD4 exome

AF:

0.0350

AC:

51163

AN:

1461184

Hom.:

1069

Cov.:

AF XY:

0.0342

AC XY:

24836

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.00532

AC:

178

AN:

33468

American (AMR)

AF:

0.00772

AC:

345

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

306

AN:

26116

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.00908

AC:

783

AN:

86186

European-Finnish (FIN)

AF:

0.0274

AC:

1462

AN:

53416

Middle Eastern (MID)

AF:

0.00819

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0416

AC:

46289

AN:

1111504

Other (OTH)

AF:

0.0290

AC:

1750

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2446

4892

7338

9784

12230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1720

3440

5160

6880

8600

<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:

0.0230

AC:

3503

AN:

152236

Hom.:

Cov.:

AF XY:

0.0224

AC XY:

1671

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00660

AC:

274

AN:

41542

American (AMR)

AF:

0.0175

AC:

267

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00954

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0268

AC:

285

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0375

AC:

2549

AN:

67994

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0314

Hom.:

386

Bravo

AF:

0.0214

TwinsUK

AF:

0.0458

AC:

170

ALSPAC

AF:

0.0516

AC:

199

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0388

AC:

334

ExAC

AF:

0.0222

AC:

2697

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0343

EpiControl

AF:

0.0332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21789270, 26691890, 22421107, 27873212, 22906531, 26222560, 28089742, 17145954, 26745718, 19105210, 26832773, 12578864, 28222214, 28418605, 28884020, 28402931, 30070759, 32162184, 33025555, 33488516) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Thyroid cancer, nonmedullary, 5

Uncertain:1

May 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

FACTOR VII-ACTIVATING PROTEASE MARBURG I POLYMORPHISM

Benign:1

Nov 19, 2015

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Factor VII Marburg I Variant Thrombophilia

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Venous thromboembolism, susceptibility to

Other:1

Nov 19, 2015

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

THYROID CANCER, NONMEDULLARY, 5, SUSCEPTIBILITY TO

Other:1

Nov 19, 2015

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0092

T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.6

.;M

PhyloP100

9.3

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.32

MPC

0.058

ClinPred

0.023

GERP RS

5.9

Varity_R

0.95

gMVP

0.89

Mutation Taster

=93/7

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