chr17-5433125-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001212.4(C1QBP):​c.739G>C​(p.Gly247Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. G247W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

C1QBP
NM_001212.4 missense

Scores

13
5
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.78

Publications

8 publications found
Variant links:
Genes affected
C1QBP (HGNC:1243): (complement C1q binding protein) The human complement subcomponent C1q associates with C1r and C1s in order to yield the first component of the serum complement system. The protein encoded by this gene is known to bind to the globular heads of C1q molecules and inhibit C1 activation. This protein has also been identified as the p32 subunit of pre-mRNA splicing factor SF2, as well as a hyaluronic acid-binding protein. [provided by RefSeq, Jul 2008]
RPAIN (HGNC:28641): (RPA interacting protein) Predicted to enable metal ion binding activity. Acts upstream of or within several processes, including DNA metabolic process; protein import into nucleus; and response to UV. Located in PML body; cytoplasm; and fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-5433125-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 441244.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C1QBPNM_001212.4 linkc.739G>C p.Gly247Arg missense_variant Exon 6 of 6 ENST00000225698.8 NP_001203.1 Q07021
RPAINNM_001033002.4 linkc.*554C>G downstream_gene_variant ENST00000381209.8 NP_001028174.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C1QBPENST00000225698.8 linkc.739G>C p.Gly247Arg missense_variant Exon 6 of 6 1 NM_001212.4 ENSP00000225698.4 Q07021
RPAINENST00000381209.8 linkc.*554C>G downstream_gene_variant 1 NM_001033002.4 ENSP00000370606.3 Q86UA6-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251268
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461854
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;.;D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Pathogenic
3.6
H;.;.
PhyloP100
7.8
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.6
D;.;.
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;.;.
Sift4G
Uncertain
0.0050
D;D;.
Polyphen
1.0
D;.;.
Vest4
0.95
MutPred
0.80
Gain of solvent accessibility (P = 0.019);.;.;
MVP
0.72
MPC
1.1
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.93
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1394499137; hg19: chr17-5336445; API