3-186672838-C-T

Position:

chr3-186672838-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000412.5(HRG):c.610C>T(p.Pro204Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,606,904 control chromosomes in the GnomAD database, including 109,148 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.43 ( 14941 hom., cov: 32)

Exomes 𝑓: 0.35 ( 94207 hom. )

Consequence

HRG
NM_000412.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.14

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.45819E-5).

BP6

Variant 3-186672838-C-T is Benign according to our data. Variant chr3-186672838-C-T is described in ClinVar as [Benign]. Clinvar id is 1285353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-186672838-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRG	NM_000412.5 link	c.610C>T	p.Pro204Ser	missense_variant	5/7	ENST00000232003.5	NP_000403.1	P04196
HRG	XM_005247415.5 link	c.610C>T	p.Pro204Ser	missense_variant	5/7		XP_005247472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5 link	c.610C>T	p.Pro204Ser	missense_variant	5/7	1	NM_000412.5	ENSP00000232003.4		P04196

Frequencies

GnomAD3 genomes

AF:

0.426

AC:

64693

AN:

151790

Hom.:

14924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.594

Gnomad AMI

AF:

0.461

Gnomad AMR

AF:

0.418

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.457

Gnomad FIN

AF:

0.284

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.418

GnomAD3 exomes

AF:

0.382

AC:

95937

AN:

251218

Hom.:

19555

AF XY:

0.380

AC XY:

51646

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.604

Gnomad AMR exome

AF:

0.347

Gnomad ASJ exome

AF:

0.391

Gnomad EAS exome

AF:

0.548

Gnomad SAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.274

Gnomad NFE exome

AF:

0.335

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.352

AC:

512853

AN:

1454996

Hom.:

94207

Cov.:

AF XY:

0.355

AC XY:

256927

AN XY:

724144

show subpopulations

Gnomad4 AFR exome

AF:

0.615

Gnomad4 AMR exome

AF:

0.352

Gnomad4 ASJ exome

AF:

0.394

Gnomad4 EAS exome

AF:

0.511

Gnomad4 SAS exome

AF:

0.447

Gnomad4 FIN exome

AF:

0.277

Gnomad4 NFE exome

AF:

0.332

Gnomad4 OTH exome

AF:

0.385

GnomAD4 genome

AF:

0.426

AC:

64754

AN:

151908

Hom.:

14941

Cov.:

AF XY:

0.426

AC XY:

31619

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.594

Gnomad4 AMR

AF:

0.418

Gnomad4 ASJ

AF:

0.386

Gnomad4 EAS

AF:

0.557

Gnomad4 SAS

AF:

0.457

Gnomad4 FIN

AF:

0.284

Gnomad4 NFE

AF:

0.337

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.361

Hom.:

25423

Bravo

AF:

0.440

TwinsUK

AF:

0.330

AC:

1225

ALSPAC

AF:

0.336

AC:

1296

ESP6500AA

AF:

0.594

AC:

2615

ESP6500EA

AF:

0.342

AC:

2945

ExAC

AF:

0.385

AC:

46787

Asia WGS

AF:

0.489

AC:

1700

AN:

3478

EpiCase

AF:

0.352

EpiControl

AF:

0.349

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

HRG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as 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

0.053

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.13

DEOGEN2

Benign

0.066

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.23

MetaRNN

Benign

0.000065

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.5

PrimateAI

Benign

0.39

PROVEAN

Benign

3.0

REVEL

Benign

0.080

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.065

MPC

0.077

ClinPred

0.0022

GERP RS

4.3

Varity_R

0.023

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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