rs121918122

Variant names:

• chr3-186669945-G-A
• rs121918122
• NM_000412.5:c.308G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000412.5(HRG):​c.308G>A​(p.Gly103Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,419,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G103R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HRG NM_000412.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.91
• Publications: 5 publications found

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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-186669945-G-A is Pathogenic according to our data. Variant chr3-186669945-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14914.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000412.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRG	NM_000412.5	MANE Select	c.308G>A	p.Gly103Glu	missense	Exon 3 of 7	NP_000403.1	P04196

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRG	ENST00000232003.5	TSL:1 MANE Select	c.308G>A	p.Gly103Glu	missense	Exon 3 of 7	ENSP00000232003.4	P04196
	HRG	ENST00000887868.1		c.416G>A	p.Gly139Glu	missense	Exon 4 of 8	ENSP00000557927.1
	HRG	ENST00000887859.1		c.416G>A	p.Gly139Glu	missense	Exon 4 of 8	ENSP00000557918.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419586 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 708870

African (AFR) AF: 0.00 AC: 0 AN: 32632

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 85346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075288

Other (OTH) AF: 0.00 AC: 0 AN: 58820

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.022)
MVP		0.75
MPC		0.49
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.55
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs121918122; hg19: chr3-186387734;