3-186669943-C-T

Position:

• chr3-186669943-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000412.5(HRG):​c.306C>T​(p.Ile102=) 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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 939 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRG	NM_000412.5	c.306C>T	p.Ile102=	synonymous_variant	3/7	ENST00000232003.5	NP_000403.1
HRG-AS1	XR_924801.3	n.291-18072G>A		intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5	c.306C>T	p.Ile102=	synonymous_variant	3/7		XP_005247472.1
HRG-AS1	XR_001741059.2	n.291-18072G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5	c.306C>T	p.Ile102=	synonymous_variant	3/7	1	NM_000412.5	ENSP00000232003	P1
HRG-AS1	ENST00000630178.2	n.238+48524G>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.00169 AC: 424 AN: 250862 Hom.: 3 AF XY: 0.00120 AC XY: 163 AN XY: 135560

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000939

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000767

Gnomad4 OTH exome AF: 0.00152

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

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00234 Hom.: 1

Bravo AF: 0.00731

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.77
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs73886012; hg19: chr3-186387732;