3-186671646-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000412.5(HRG):ā€‹c.415A>Gā€‹(p.Lys139Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

HRG
NM_000412.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.32833594).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HRGNM_000412.5 linkuse as main transcriptc.415A>G p.Lys139Glu missense_variant 4/7 ENST00000232003.5 NP_000403.1
HRG-AS1XR_924801.3 linkuse as main transcriptn.291-19775T>C intron_variant, non_coding_transcript_variant
HRGXM_005247415.5 linkuse as main transcriptc.415A>G p.Lys139Glu missense_variant 4/7 XP_005247472.1
HRG-AS1XR_001741059.2 linkuse as main transcriptn.291-19775T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HRGENST00000232003.5 linkuse as main transcriptc.415A>G p.Lys139Glu missense_variant 4/71 NM_000412.5 ENSP00000232003 P1
HRG-AS1ENST00000630178.2 linkuse as main transcriptn.238+46821T>C intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251292
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135798
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000326
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461790
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2023The c.415A>G (p.K139E) alteration is located in exon 4 (coding exon 4) of the HRG gene. This alteration results from a A to G substitution at nucleotide position 415, causing the lysine (K) at amino acid position 139 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
21
DANN
Benign
0.93
DEOGEN2
Benign
0.18
T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.33
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
0.98
N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.17
Sift
Benign
0.53
T
Sift4G
Benign
0.061
T
Polyphen
1.0
D
Vest4
0.45
MutPred
0.43
Loss of ubiquitination at K139 (P = 0.0134);
MVP
0.62
MPC
0.20
ClinPred
0.51
D
GERP RS
4.2
Varity_R
0.20
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs774359835; hg19: chr3-186389435; API