3-186677783-A-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.1478A>T(p.Asn493Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 1,613,568 control chromosomes in the GnomAD database, including 215,001 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 0.56 ( 25079 hom., cov: 32)

Exomes 𝑓: 0.50 ( 189922 hom. )

Consequence

HRG
NM_000412.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.92

Publications

46 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=1.0294835E-6).

BP6

Variant 3-186677783-A-T is Benign according to our data. Variant chr3-186677783-A-T is described in ClinVar as Benign. ClinVar VariationId is 1285355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRG	NM_000412.5 link	c.1478A>T	p.Asn493Ile	missense_variant	Exon 7 of 7	ENST00000232003.5	NP_000403.1	P04196
HRG	XM_005247415.5 link	c.1502A>T	p.Asn501Ile	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.1478A>T	p.Asn493Ile	missense_variant	Exon 7 of 7	1	NM_000412.5	ENSP00000232003.4		P04196

Frequencies

GnomAD3 genomes

AF:

0.565

AC:

85808

AN:

151930

Hom.:

25050

Cov.:

show subpopulations

Gnomad AFR

AF:

0.684

Gnomad AMI

AF:

0.504

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.803

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.474

Gnomad MID

AF:

0.560

Gnomad NFE

AF:

0.485

Gnomad OTH

AF:

0.555

GnomAD2 exomes

AF:

0.552

AC:

138703

AN:

251324

AF XY:

0.548

show subpopulations

Gnomad AFR exome

AF:

0.693

Gnomad AMR exome

AF:

0.602

Gnomad ASJ exome

AF:

0.508

Gnomad EAS exome

AF:

0.796

Gnomad FIN exome

AF:

0.465

Gnomad NFE exome

AF:

0.481

Gnomad OTH exome

AF:

0.542

GnomAD4 exome

AF:

0.505

AC:

737811

AN:

1461520

Hom.:

189922

Cov.:

AF XY:

0.507

AC XY:

368845

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.700

AC:

23444

AN:

33474

American (AMR)

AF:

0.599

AC:

26793

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

13369

AN:

26134

East Asian (EAS)

AF:

0.772

AC:

30637

AN:

39698

South Asian (SAS)

AF:

0.607

AC:

52339

AN:

86240

European-Finnish (FIN)

AF:

0.468

AC:

24999

AN:

53412

Middle Eastern (MID)

AF:

0.562

AC:

3242

AN:

5766

European-Non Finnish (NFE)

AF:

0.477

AC:

530834

AN:

1111710

Other (OTH)

AF:

0.533

AC:

32154

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

20491

40982

61473

81964

102455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15856

31712

47568

63424

79280

<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:

0.565

AC:

85890

AN:

152048

Hom.:

25079

Cov.:

AF XY:

0.567

AC XY:

42164

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.684

AC:

28376

AN:

41492

American (AMR)

AF:

0.582

AC:

8893

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1770

AN:

3468

East Asian (EAS)

AF:

0.802

AC:

4140

AN:

5160

South Asian (SAS)

AF:

0.613

AC:

2955

AN:

4818

European-Finnish (FIN)

AF:

0.474

AC:

5006

AN:

10552

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.485

AC:

32949

AN:

67958

Other (OTH)

AF:

0.557

AC:

1177

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1887

3773

5660

7546

9433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

728

1456

2184

2912

3640

<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:

0.500

Hom.:

14793

Bravo

AF:

0.577

TwinsUK

AF:

0.479

AC:

1776

ALSPAC

AF:

0.477

AC:

1839

ESP6500AA

AF:

0.682

AC:

3006

ESP6500EA

AF:

0.485

AC:

4171

ExAC

AF:

0.552

AC:

67004

Asia WGS

AF:

0.714

AC:

2483

AN:

3478

EpiCase

AF:

0.492

EpiControl

AF:

0.490

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

0.034

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.040

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.2

PhyloP100

1.9

PrimateAI

Benign

0.47

PROVEAN

Benign

3.4

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.053

MPC

0.096

ClinPred

0.0026

GERP RS

4.6

Varity_R

0.094

gMVP

0.067

Mutation Taster

=100/0

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