rs1042445

Variant names:

• chr3-186677647-C-T
• rs1042445
• NM_000412.5:c.1342C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-186677647-C-T
• chr3-186677647-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.405
• Publications: 37 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000412.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRG	NM_000412.5	MANE Select	c.1342C>T	p.Arg448Cys	missense	Exon 7 of 7	NP_000403.1	P04196

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRG	ENST00000232003.5	TSL:1 MANE Select	c.1342C>T	p.Arg448Cys	missense	Exon 7 of 7	ENSP00000232003.4	P04196
	HRG	ENST00000887868.1		c.1474C>T	p.Arg492Cys	missense	Exon 8 of 8	ENSP00000557927.1
	HRG	ENST00000887859.1		c.1450C>T	p.Arg484Cys	missense	Exon 8 of 8	ENSP00000557918.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38028 AN: 151840 Hom.: 4933 Cov.: 31

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

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.: 59 AF XY: 0.243 AC XY: 176924 AN XY: 727132

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

GnomAD4 genome AF: 0.250 AC: 38045 AN: 151958 Hom.: 4932 Cov.: 31 AF XY: 0.255 AC XY: 18922 AN XY: 74266

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: 75 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15617 AN: 67938

Other (OTH) AF: 0.254 AC: 537 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.6
DANN	Benign	0.47
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00081	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.41	N
PhyloP100		-0.41
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.022
Sift	Benign	0.27	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.016
MPC		0.10
ClinPred		0.0042	T
GERP RS		2.4
Varity_R		0.073
gMVP		0.14
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042445; hg19: chr3-186395436; COSMIC: COSV51645137; COSMIC: COSV51645137;