3-186669943-C-T

Variant names:

• chr3-186669943-C-T
• rs73886012
• NM_000412.5:c.306C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000412.5(HRG):​c.306C>T​(p.Ile102Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,565,278 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (7 hom.)
• Consequence: HRG NM_000412.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 3-186669943-C-T is Benign according to our data. Variant chr3-186669943-C-T is described in ClinVar as Benign. ClinVar VariationId is 786027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00617 (939/152262) while in subpopulation AFR AF = 0.0211 (876/41532). AF 95% confidence interval is 0.0199. There are 9 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 939 AD gene.

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.306C>T	p.Ile102Ile	synonymous	Exon 3 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.306C>T	p.Ile102Ile	synonymous	Exon 3 of 7	ENSP00000232003.4	P04196
	HRG	ENST00000887868.1		c.414C>T	p.Ile138Ile	synonymous	Exon 4 of 8	ENSP00000557927.1
	HRG	ENST00000887859.1		c.414C>T	p.Ile138Ile	synonymous	Exon 4 of 8	ENSP00000557918.1

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 943 AN: 152144 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00169 AC: 424 AN: 250862 AF XY: 0.00120

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000661 AC: 934 AN: 1413016 Hom.: 7 Cov.: 25 AF XY: 0.000587 AC XY: 414 AN XY: 705836

African (AFR) AF: 0.0211 AC: 685 AN: 32458

American (AMR) AF: 0.00154 AC: 69 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000939 AC: 8 AN: 85210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.0000767 AC: 82 AN: 1069346

Other (OTH) AF: 0.00152 AC: 89 AN: 58614

GnomAD4 genome AF: 0.00617 AC: 939 AN: 152262 Hom.: 9 Cov.: 32 AF XY: 0.00590 AC XY: 439 AN XY: 74466

African (AFR) AF: 0.0211 AC: 876 AN: 41532

American (AMR) AF: 0.00274 AC: 42 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00238 Hom.: 1

Bravo AF: 0.00731

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.77
DANN	Benign	0.80
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs73886012; hg19: chr3-186387732;