chr3-186668924-G-T

Variant names:

• chr3-186668924-G-T
• rs80205675
• NM_000412.5:c.184-11G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000412.5(HRG):​c.184-11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0073 in 1,472,238 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (49 hom.)
• Consequence: HRG NM_000412.5 intron
• Scores: Splicing: ADA: 0.0001642
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.171

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-186668924-G-T is Benign according to our data. Variant chr3-186668924-G-T is described in ClinVar as [Benign]. Clinvar id is 1234952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRG	NM_000412.5	c.184-11G>T		intron_variant	Intron 1 of 6	ENST00000232003.5	NP_000403.1
HRG	XM_005247415.5	c.184-11G>T		intron_variant	Intron 1 of 6		XP_005247472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5	c.184-11G>T		intron_variant	Intron 1 of 6	1	NM_000412.5	ENSP00000232003.4

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 770 AN: 152002 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00379

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00880

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00511 AC: 1284 AN: 251068 AF XY: 0.00494

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00871

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00756 AC: 9981 AN: 1320122 Hom.: 49 Cov.: 20 AF XY: 0.00722 AC XY: 4803 AN XY: 664888

Gnomad4 AFR exome AF: 0.000879 AC: 27 AN: 30716

Gnomad4 AMR exome AF: 0.00458 AC: 204 AN: 44566

Gnomad4 ASJ exome AF: 0.000277 AC: 7 AN: 25242

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39036

Gnomad4 SAS exome AF: 0.000767 AC: 64 AN: 83424

Gnomad4 FIN exome AF: 0.00378 AC: 201 AN: 53190

Gnomad4 NFE exome AF: 0.00928 AC: 9124 AN: 982810

Gnomad4 Remaining exome AF: 0.00615 AC: 342 AN: 55636

GnomAD4 genome AF: 0.00506 AC: 770 AN: 152116 Hom.: 4 Cov.: 32 AF XY: 0.00452 AC XY: 336 AN XY: 74364

Gnomad4 AFR AF: 0.00128 AC: 0.00127674 AN: 0.00127674

Gnomad4 AMR AF: 0.00406 AC: 0.00405759 AN: 0.00405759

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000831 AC: 0.00083091 AN: 0.00083091

Gnomad4 FIN AF: 0.00379 AC: 0.0037886 AN: 0.0037886

Gnomad4 NFE AF: 0.00880 AC: 0.00879645 AN: 0.00879645

Gnomad4 OTH AF: 0.00570 AC: 0.00569801 AN: 0.00569801

Alfa AF: 0.00742 Hom.: 5

Bravo AF: 0.00497

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.7
DANN	Benign	0.83
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.17
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: rs80205675; hg19: chr3-186386713;