3-186666156-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000412.5(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 NM_000412.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.44

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

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015212595).
• BP6: Variant 3-186666156-G-A is Benign according to our data. Variant chr3-186666156-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 809579.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High AC in GnomAd at 476 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152208 Hom.: 3 Cov.: 32

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.: 1 AF XY: 0.00251 AC XY: 341 AN XY: 135862

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.: 16 Cov.: 31 AF XY: 0.00367 AC XY: 2667 AN XY: 727230

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.: 3 Cov.: 32 AF XY: 0.00309 AC XY: 230 AN XY: 74480

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.: 2

Bravo AF: 0.00304

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00259 AC: 315

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

HRG: BP4, BS2 -

HRG-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.67	D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.74
MPC		0.26
ClinPred		0.029	T
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

Other links and lift over

dbSNP: rs114895145; hg19: chr3-186383945;