rs1042445

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000412.5(HRG):​c.1342C>A​(p.Arg448Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HRG
NM_000412.5 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.405
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-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.062037617).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HRGNM_000412.5 linkuse as main transcriptc.1342C>A p.Arg448Ser missense_variant 7/7 ENST00000232003.5
HRG-AS1XR_924801.3 linkuse as main transcriptn.291-25776G>T intron_variant, non_coding_transcript_variant
HRGXM_005247415.5 linkuse as main transcriptc.1366C>A p.Arg456Ser missense_variant 7/7
HRG-AS1XR_001741059.2 linkuse as main transcriptn.291-25776G>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HRGENST00000232003.5 linkuse as main transcriptc.1342C>A p.Arg448Ser missense_variant 7/71 NM_000412.5 P1
HRG-AS1ENST00000630178.2 linkuse as main transcriptn.238+40820G>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151912
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461822
Hom.:
0
Cov.:
59
AF XY:
0.00000138
AC XY:
1
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151912
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74168
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.87
CADD
Benign
0.39
DANN
Benign
0.32
DEOGEN2
Benign
0.053
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.19
T
M_CAP
Benign
0.0024
T
MetaRNN
Benign
0.062
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.20
T
PROVEAN
Benign
0.37
N
REVEL
Benign
0.014
Sift
Benign
0.51
T
Sift4G
Benign
0.66
T
Polyphen
0.0010
B
Vest4
0.037
MutPred
0.28
Loss of MoRF binding (P = 0.0215);
MVP
0.14
MPC
0.086
ClinPred
0.037
T
GERP RS
2.4
Varity_R
0.094
gMVP
0.13

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

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

Other links and lift over

dbSNP: rs1042445; hg19: chr3-186395436; API