Genetic Variant NM_001212.4:c.739G>A (chr17-5433125-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

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>A(p.Gly247Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

C1QBP
NM_001212.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.78

Publications

0 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]

C1QBP links:

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]

RPAIN links:

ENSG00000263272 (HGNC:):

ENSG00000263272 links:

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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 VariationId is 441244.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001212.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1QBP	NM_001212.4	MANE Select	c.739G>A	p.Gly247Arg	missense	Exon 6 of 6	NP_001203.1	Q07021
RPAIN	NM_001033002.4	MANE Select	c.*554C>T		downstream_gene	N/A	NP_001028174.2	Q86UA6-1
RPAIN	NM_001160244.2		c.*554C>T		downstream_gene	N/A	NP_001153716.1	Q86UA6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1QBP	ENST00000225698.8	TSL:1 MANE Select	c.739G>A	p.Gly247Arg	missense	Exon 6 of 6	ENSP00000225698.4	Q07021
C1QBP	ENST00000574444.5	TSL:3	c.427G>A	p.Gly143Arg	missense	Exon 6 of 6	ENSP00000460308.1	I3L3B0
C1QBP	ENST00000570805.1	TSL:3	c.427G>A	p.Gly143Arg	missense	Exon 6 of 6	ENSP00000460638.1	I3L3Q7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.6

PhyloP100

7.8

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.95

MutPred

0.80

Gain of solvent accessibility (P = 0.019)

MVP

0.72

MPC

1.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.93

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over