chr3-186671620-C-T

Position:

chr3-186671620-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000412.5(HRG):c.392-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,666 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00099 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HRG
NM_000412.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003244

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.123

Variant links:

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 links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 3-186671620-C-T is Benign according to our data. Variant chr3-186671620-C-T is described in ClinVar as [Benign]. Clinvar id is 2581309.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
HRG	NM_000412.5 linkuse as main transcript	c.392-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000232003.5
HRG-AS1	XR_924801.3 linkuse as main transcript	n.291-19749G>A	intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5 linkuse as main transcript	c.392-3C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
HRG-AS1	XR_001741059.2 linkuse as main transcript	n.291-19749G>A	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRG	ENST00000232003.5 linkuse as main transcript	c.392-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000412.5	P1
HRG-AS1	ENST00000630178.2 linkuse as main transcript	n.238+46847G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000953

AC:

145

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000223

AC:

AN:

251240

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000119

AC:

174

AN:

1461370

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00379

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000991

AC:

151

AN:

152296

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00347

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000736

Hom.:

Bravo

AF:

0.00117

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 23, 2023

Variant summary: HRG c.392-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00095 in 152178 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.392-3C>T in individuals affected with Hereditary Thrombophilia Due To Congenital Histidine-Rich (poly-L) Glycoprotein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.4

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.016

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over