3-186666156-G-A

Position:

chr3-186666156-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000232003.5(HRG):c.125G>A(p.Arg42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,178 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 16 hom. )

Consequence

HRG
ENST00000232003.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.44

Variant links:

Genes affected

HRG (HGNC:5181): (histidine rich glycoprotein) This histidine-rich glycoprotein contains two cystatin-like domains and is located in plasma and platelets. The physiological function has not been determined but it is known that the protein binds heme, dyes and divalent metal ions. The encoded protein also has a peptide that displays antimicrobial activity against C. albicans, E. coli, S. aureus, P. aeruginosa, and E. faecalis. It can inhibit rosette formation and interacts with heparin, thrombospondin and plasminogen. Two of the protein's effects, the inhibition of fibrinolysis and the reduction of inhibition of coagulation, indicate a potential prothrombotic effect. Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels. [provided by RefSeq, Nov 2014]

HRG links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015212595).

BS2

High AC in GnomAd4 at 476 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HRG	NM_000412.5 linkuse as main transcript	c.125G>A	p.Arg42Gln	missense_variant	1/7	ENST00000232003.5	NP_000403.1
HRG-AS1	XR_924801.3 linkuse as main transcript	n.291-14285C>T		intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5 linkuse as main transcript	c.125G>A	p.Arg42Gln	missense_variant	1/7		XP_005247472.1
HRG-AS1	XR_001741059.2 linkuse as main transcript	n.291-14285C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5 linkuse as main transcript	c.125G>A	p.Arg42Gln	missense_variant	1/7	1	NM_000412.5	ENSP00000232003	P1
HRG-AS1	ENST00000630178.2 linkuse as main transcript	n.238+52311C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

476

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00466

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00259

AC:

651

AN:

251374

Hom.:

AF XY:

0.00251

AC XY:

341

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.00432

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00381

AC:

5567

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

2667

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00300

Gnomad4 NFE exome

AF:

0.00455

Gnomad4 OTH exome

AF:

0.00290

GnomAD4 genome

AF:

0.00312

AC:

476

AN:

152326

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.00466

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00394

Hom.:

Bravo

AF:

0.00304

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00259

AC:

315

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	HRG: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Thrombus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

HRG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.78

M_CAP

Benign

0.018

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.67

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.17

Sift

Benign

0.11

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.42

MVP

0.74

MPC

0.26

ClinPred

0.029

GERP RS

5.5

Varity_R

0.21

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over