3-186677647-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000412.5(HRG):c.1342C>T(p.Arg448Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,694 control chromosomes in the GnomAD database, including 48,813 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 4932 hom., cov: 31)

Exomes 𝑓: 0.24 ( 43881 hom. )

Consequence

HRG
NM_000412.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.405

Publications

37 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010050803).

BP6

Variant 3-186677647-C-T is Benign according to our data. Variant chr3-186677647-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRG	NM_000412.5 link	c.1342C>T	p.Arg448Cys	missense_variant	Exon 7 of 7	ENST00000232003.5	NP_000403.1	P04196
HRG	XM_005247415.5 link	c.1366C>T	p.Arg456Cys	missense_variant	Exon 7 of 7		XP_005247472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5 link	c.1342C>T	p.Arg448Cys	missense_variant	Exon 7 of 7	1	NM_000412.5	ENSP00000232003.4		P04196

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

38028

AN:

151840

Hom.:

4933

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.302

Gnomad SAS

AF:

0.335

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.252

GnomAD2 exomes

AF:

0.271

AC:

68022

AN:

250950

AF XY:

0.270

show subpopulations

Gnomad AFR exome

AF:

0.253

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.239

Gnomad EAS exome

AF:

0.297

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.241

AC:

352309

AN:

1461736

Hom.:

43881

Cov.:

AF XY:

0.243

AC XY:

176924

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.261

AC:

8742

AN:

33476

American (AMR)

AF:

0.342

AC:

15272

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6192

AN:

26134

East Asian (EAS)

AF:

0.321

AC:

12725

AN:

39692

South Asian (SAS)

AF:

0.337

AC:

29035

AN:

86246

European-Finnish (FIN)

AF:

0.280

AC:

14938

AN:

53418

Middle Eastern (MID)

AF:

0.249

AC:

1434

AN:

5768

European-Non Finnish (NFE)

AF:

0.224

AC:

249181

AN:

1111890

Other (OTH)

AF:

0.245

AC:

14790

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16246

32492

48738

64984

81230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8706

17412

26118

34824

43530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.250

AC:

38045

AN:

151958

Hom.:

4932

Cov.:

AF XY:

0.255

AC XY:

18922

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.254

AC:

10537

AN:

41438

American (AMR)

AF:

0.268

AC:

4091

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

832

AN:

3468

East Asian (EAS)

AF:

0.302

AC:

1562

AN:

5170

South Asian (SAS)

AF:

0.333

AC:

1604

AN:

4814

European-Finnish (FIN)

AF:

0.286

AC:

3021

AN:

10560

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15617

AN:

67938

Other (OTH)

AF:

0.254

AC:

537

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1455

2910

4366

5821

7276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.235

Hom.:

15697

Bravo

AF:

0.250

TwinsUK

AF:

0.230

AC:

854

ALSPAC

AF:

0.233

AC:

897

ESP6500AA

AF:

0.250

AC:

1101

ESP6500EA

AF:

0.227

AC:

1955

ExAC

AF:

0.271

AC:

32845

Asia WGS

AF:

0.322

AC:

1120

AN:

3478

EpiCase

AF:

0.230

EpiControl

AF:

0.236

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.6

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.041

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00081

LIST_S2

Benign

0.29

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.41

PhyloP100

-0.41

PrimateAI

Benign

0.21

PROVEAN

Benign

0.28

REVEL

Benign

0.022

Sift

Benign

0.27

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.016

MPC

0.10

ClinPred

0.0042

GERP RS

2.4

Varity_R

0.073

gMVP

0.14

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over