3-186671620-C-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.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

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=-0.76).
• 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 GnomAd at 145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRG	NM_000412.5	c.392-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000232003.5
HRG-AS1	XR_924801.3	n.291-19749G>A		intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5	c.392-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
HRG-AS1	XR_001741059.2	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	c.392-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000412.5	P1
HRG-AS1	ENST00000630178.2	n.238+46847G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152178 Hom.: 1 Cov.: 31

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: 56 AN: 251240 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135762

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.: 0 Cov.: 31 AF XY: 0.000118 AC XY: 86 AN XY: 726986

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.: 1 Cov.: 31 AF XY: 0.000967 AC XY: 72 AN XY: 74466

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.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

Other links and lift over

dbSNP: rs146676859; hg19: chr3-186389409;