17-5433039-GA-AG

Variant names:

• chr17-5433039-GA-AG
• NM_001212.4:c.824_825delTCinsCT
• C1QBP p.Leu275Pro

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM5 PP3

The NM_001212.4(C1QBP):​c.824_825delTCinsCT​(p.Leu275Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L275F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1QBP NM_001212.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.18
• Publications: 0 publications found

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]

ENSG00000263272 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_001212.4 (C1QBP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-5433041-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 441245.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QBP	NM_001212.4	MANE Select	c.824_825delTCinsCT	p.Leu275Pro	missense	N/A	NP_001203.1	Q07021
	RPAIN	NM_001033002.4	MANE Select	c.*468_*469delGAinsAG		downstream_gene	N/A	NP_001028174.2	Q86UA6-1
	RPAIN	NM_001160244.2		c.*468_*469delGAinsAG		downstream_gene	N/A	NP_001153716.1	Q86UA6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QBP	ENST00000225698.8	TSL:1 MANE Select	c.824_825delTCinsCT	p.Leu275Pro	missense	N/A	ENSP00000225698.4	Q07021
	C1QBP	ENST00000574444.5	TSL:3	c.512_513delTCinsCT	p.Leu171Pro	missense	N/A	ENSP00000460308.1	I3L3B0
	C1QBP	ENST00000570805.1	TSL:3	c.512_513delTCinsCT	p.Leu171Pro	missense	N/A	ENSP00000460638.1	I3L3Q7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-5336359;