rs7080536

Variant names:

• chr10-113588287-G-A
• rs7080536
• NM_004132.5:c.1601G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 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 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:2
• Conservation: PhyloP100: 9.29
• Publications: 102 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004132.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HABP2	NM_004132.5	MANE Select	c.1601G>A	p.Gly534Glu	missense	Exon 13 of 13	NP_004123.1	Q14520-1
	HABP2	NM_001177660.3		c.1523G>A	p.Gly508Glu	missense	Exon 13 of 13	NP_001171131.1	Q14520-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HABP2	ENST00000351270.4	TSL:1 MANE Select	c.1601G>A	p.Gly534Glu	missense	Exon 13 of 13	ENSP00000277903.4	Q14520-1
	HABP2	ENST00000883707.1		c.1601G>A	p.Gly534Glu	missense	Exon 14 of 14	ENSP00000553766.1
	HABP2	ENST00000542051.5	TSL:2	c.1523G>A	p.Gly508Glu	missense	Exon 13 of 13	ENSP00000443283.1	Q14520-2

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

GnomAD2 exomes AF: 0.0223 AC: 5608 AN: 251244 AF XY: 0.0231

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

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: 3 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: 47 AN: 5740

European-Non Finnish (NFE) AF: 0.0416 AC: 46289 AN: 1111504

Other (OTH) AF: 0.0290 AC: 1750 AN: 60366

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

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: 40 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00954 AC: 46 AN: 4824

European-Finnish (FIN) AF: 0.0268 AC: 285 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0375 AC: 2549 AN: 67994

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

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: 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Factor VII Marburg I Variant Thrombophilia (1)
-	-	1	FACTOR VII-ACTIVATING PROTEASE MARBURG I POLYMORPHISM (1)
-	1	-	Thyroid cancer, nonmedullary, 5 (1)
-	-	-	THYROID CANCER, NONMEDULLARY, 5, SUSCEPTIBILITY TO (1)
-	-	-	Venous thromboembolism, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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