Genetic Variant HRG:p.Ser79Trp (chr3-186668987-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000412.5(HRG):c.236C>G(p.Ser79Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,612,112 control chromosomes in the GnomAD database, including 70 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S79L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0065 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 59 hom. )

Consequence

HRG
NM_000412.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.763

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060816407).

BP6

Variant 3-186668987-C-G is Benign according to our data. Variant chr3-186668987-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2654336.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 997 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRG	NM_000412.5 link	c.236C>G	p.Ser79Trp	missense_variant	Exon 2 of 7	ENST00000232003.5	NP_000403.1	P04196
HRG	XM_005247415.5 link	c.236C>G	p.Ser79Trp	missense_variant	Exon 2 of 7		XP_005247472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5 link	c.236C>G	p.Ser79Trp	missense_variant	Exon 2 of 7	1	NM_000412.5	ENSP00000232003.4		P04196

Frequencies

GnomAD3 genomes

AF:

0.00655

AC:

997

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0323

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00742

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00741

AC:

1861

AN:

251264

Hom.:

AF XY:

0.00721

AC XY:

979

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00566

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.00875

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.00715

AC:

10437

AN:

1459874

Hom.:

Cov.:

AF XY:

0.00696

AC XY:

5055

AN XY:

726372

show subpopulations

Gnomad4 AFR exome

AF:

0.000867

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.0283

Gnomad4 NFE exome

AF:

0.00741

Gnomad4 OTH exome

AF:

0.00562

GnomAD4 genome

AF:

0.00655

AC:

997

AN:

152238

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

535

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0323

Gnomad4 NFE

AF:

0.00742

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00378

Hom.:

Bravo

AF:

0.00453

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00687

AC:

834

EpiCase

AF:

0.00693

EpiControl

AF:

0.00818

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HRG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.4

DANN

Benign

0.76

DEOGEN2

Benign

0.15

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.32

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.66

REVEL

Benign

0.024

Sift

Benign

0.044

Sift4G

Uncertain

0.051

Polyphen

0.0050

Vest4

0.35

MVP

0.29

MPC

0.11

ClinPred

0.00097

GERP RS

1.8

Varity_R

0.044

gMVP

0.26

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