3-186668987-C-G

Position:

• chr3-186668987-C-G

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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S79L) has been classified 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

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 (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 id is 2654336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 997 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRG	NM_000412.5	c.236C>G	p.Ser79Trp	missense_variant	2/7	ENST00000232003.5	NP_000403.1
HRG-AS1	XR_924801.3	n.291-17116G>C		intron_variant, non_coding_transcript_variant
HRG	XM_005247415.5	c.236C>G	p.Ser79Trp	missense_variant	2/7		XP_005247472.1
HRG-AS1	XR_001741059.2	n.291-17116G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRG	ENST00000232003.5	c.236C>G	p.Ser79Trp	missense_variant	2/7	1	NM_000412.5	ENSP00000232003	P1
HRG-AS1	ENST00000630178.2	n.238+49480G>C		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.00741 AC: 1861 AN: 251264 Hom.: 17 AF XY: 0.00721 AC XY: 979 AN XY: 135792

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 SAS exome AF: 0.000751

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

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.00741

Gnomad4 OTH exome AF: 0.00562

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

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.00742

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00378 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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

HRG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

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