3-186668987-C-G

Variant names:

• chr3-186668987-C-G
• rs4516605
• NM_000412.5:c.236C>G

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.236C>G​(p.Ser79Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,612,112 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (59 hom.)
• Consequence: HRG NM_000412.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.763
• Publications: 7 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060816407).
• BP6: Variant 3-186668987-C-G is Benign according to our data. Variant chr3-186668987-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2654336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 997 AD gene.

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.236C>G	p.Ser79Trp	missense	Exon 2 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.236C>G	p.Ser79Trp	missense	Exon 2 of 7	ENSP00000232003.4	P04196
	HRG	ENST00000887868.1		c.236C>G	p.Ser79Trp	missense	Exon 2 of 8	ENSP00000557927.1
	HRG	ENST00000887859.1		c.236C>G	p.Ser79Trp	missense	Exon 2 of 8	ENSP00000557918.1

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 997 AN: 152120 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00742

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00741 AC: 1861 AN: 251264 AF XY: 0.00721

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.00875

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00715 AC: 10437 AN: 1459874 Hom.: 59 Cov.: 30 AF XY: 0.00696 AC XY: 5055 AN XY: 726372

African (AFR) AF: 0.000867 AC: 29 AN: 33452

American (AMR) AF: 0.00203 AC: 91 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 130 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86216

European-Finnish (FIN) AF: 0.0283 AC: 1512 AN: 53414

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5760

European-Non Finnish (NFE) AF: 0.00741 AC: 8223 AN: 1110166

Other (OTH) AF: 0.00562 AC: 339 AN: 60334

GnomAD4 genome AF: 0.00655 AC: 997 AN: 152238 Hom.: 11 Cov.: 32 AF XY: 0.00719 AC XY: 535 AN XY: 74428

African (AFR) AF: 0.00113 AC: 47 AN: 41550

American (AMR) AF: 0.00314 AC: 48 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.0323 AC: 343 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00742 AC: 505 AN: 68014

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00309 Hom.: 6

Bravo AF: 0.00453

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00687 AC: 834

EpiCase AF: 0.00693

EpiControl AF: 0.00818

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
PhyloP100		0.76
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.024
Sift	Benign	0.044	D
Sift4G	Uncertain	0.051	T
Polyphen		0.0050	B
Vest4		0.35
MVP		0.29
MPC		0.11
ClinPred		0.00097	T
GERP RS		1.8
Varity_R		0.044
gMVP		0.26
Mutation Taster		=95/5	polymorphism

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: rs4516605; hg19: chr3-186386776; COSMIC: COSV105081606; COSMIC: COSV105081606;