3-186668924-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000412.5(HRG):c.184-11G>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, 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

Verdict is Benign. Variant got -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 GnomAd at 770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRG	NM_000412.5	c.184-11G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000232003.5
HRG-AS1	XR_924801.3	n.291-17053C>A		intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5	c.184-11G>T		splice_polypyrimidine_tract_variant, intron_variant
HRG-AS1	XR_001741059.2	n.291-17053C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRG	ENST00000232003.5	c.184-11G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000412.5	P1
HRG-AS1	ENST00000630178.2	n.238+49543C>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.00511 AC: 1284 AN: 251068 Hom.: 6 AF XY: 0.00494 AC XY: 670 AN XY: 135722

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 SAS exome AF: 0.000653

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

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.000277

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000767

Gnomad4 FIN exome AF: 0.00378

Gnomad4 NFE exome AF: 0.00928

Gnomad4 OTH exome AF: 0.00615

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

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00379

Gnomad4 NFE AF: 0.00880

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00755 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	9.7
Dann	Benign	0.83

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;