3-186671646-A-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_000412.5(HRG):āc.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
NM_000412.5 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 4.49
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]
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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 |
---|---|---|---|---|---|---|---|---|
HRG | NM_000412.5 | c.415A>G | p.Lys139Glu | missense_variant | 4/7 | ENST00000232003.5 | NP_000403.1 | |
HRG-AS1 | XR_924801.3 | n.291-19775T>C | intron_variant, non_coding_transcript_variant | |||||
HRG | XM_005247415.5 | c.415A>G | p.Lys139Glu | missense_variant | 4/7 | XP_005247472.1 | ||
HRG-AS1 | XR_001741059.2 | n.291-19775T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HRG | ENST00000232003.5 | c.415A>G | p.Lys139Glu | missense_variant | 4/7 | 1 | NM_000412.5 | ENSP00000232003 | P1 | |
HRG-AS1 | ENST00000630178.2 | n.238+46821T>C | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251292Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135798
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727200
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GnomAD4 genome Cov.: 31
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31
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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 submitter | clinical testing | Ambry Genetics | May 09, 2023 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K139 (P = 0.0134);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at