rs7080536

chr10-113588287-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1069 hom.)
• Consequence: HABP2 NM_004132.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, 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 [Likely_benign]. Clinvar id is 5974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-113588287-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HABP2	NM_004132.5	c.1601G>A	p.Gly534Glu	missense_variant	13/13	ENST00000351270.4
HABP2	NM_001177660.3	c.1523G>A	p.Gly508Glu	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HABP2	ENST00000351270.4	c.1601G>A	p.Gly534Glu	missense_variant	13/13	1	NM_004132.5	P1
HABP2	ENST00000542051.5	c.1523G>A	p.Gly508Glu	missense_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3501 AN: 152118 Hom.: 54 Cov.: 32

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

GnomAD3 exomes AF: 0.0223 AC: 5608 AN: 251244 Hom.: 89 AF XY: 0.0231 AC XY: 3132 AN XY: 135788

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 SAS exome AF: 0.00909

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.: 30 AF XY: 0.0342 AC XY: 24836 AN XY: 726928

Gnomad4 AFR exome AF: 0.00532

Gnomad4 AMR exome AF: 0.00772

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00908

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0416

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0230 AC: 3503 AN: 152236 Hom.: 54 Cov.: 32 AF XY: 0.0224 AC XY: 1671 AN XY: 74438

Gnomad4 AFR AF: 0.00660

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.0268

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0324 Hom.: 191

Bravo AF: 0.0214

TwinsUK AF: 0.0458 AC: 170

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0222 AC: 2697

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0343

EpiControl AF: 0.0332

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FACTOR VII-ACTIVATING PROTEASE MARBURG I POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Nov 19, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2021

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) -

Factor VII Marburg I Variant Thrombophilia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

risk factor, no assertion criteria provided

literature only

OMIM

Nov 19, 2015

- -

THYROID CANCER, NONMEDULLARY, 5, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 19, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0092	T;T
MetaSVM	Uncertain	0.39	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.60	T
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	T
GERP RS		5.9
Varity_R		0.95
gMVP		0.89

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

Other links and lift over

dbSNP: rs7080536; hg19: chr10-115348046; COSMIC: COSV63490531; COSMIC: COSV63490531;