3-186677783-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.56 (25079 hom., cov: 32)
  • Exomes 𝑓: 0.50 (189922 hom.)
• Consequence: HRG NM_000412.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.92

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 -14 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 id is 1285355.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-186677783-A-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
HRG	NM_000412.5	c.1478A>T	p.Asn493Ile	missense_variant	7/7	ENST00000232003.5
HRG-AS1	XR_924801.3	n.291-25912T>A		intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5	c.1502A>T	p.Asn501Ile	missense_variant	7/7
HRG-AS1	XR_001741059.2	n.291-25912T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRG	ENST00000232003.5	c.1478A>T	p.Asn493Ile	missense_variant	7/7	1	NM_000412.5	P1
HRG-AS1	ENST00000630178.2	n.238+40684T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85808 AN: 151930 Hom.: 25050 Cov.: 32

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

GnomAD3 exomes AF: 0.552 AC: 138703 AN: 251324 Hom.: 39675 AF XY: 0.548 AC XY: 74365 AN XY: 135822

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 SAS exome AF: 0.614

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.: 52 AF XY: 0.507 AC XY: 368845 AN XY: 727016

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.599

Gnomad4 ASJ exome AF: 0.512

Gnomad4 EAS exome AF: 0.772

Gnomad4 SAS exome AF: 0.607

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.533

GnomAD4 genome AF: 0.565 AC: 85890 AN: 152048 Hom.: 25079 Cov.: 32 AF XY: 0.567 AC XY: 42164 AN XY: 74304

Gnomad4 AFR AF: 0.684

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.802

Gnomad4 SAS AF: 0.613

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.557

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:1

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	10
Dann	Benign	0.17
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	3.4	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.096
ClinPred		0.0026	T
GERP RS		4.6
Varity_R		0.094
gMVP		0.067

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: rs1042464; hg19: chr3-186395572; COSMIC: COSV51644761; COSMIC: COSV51644761;