Genetic Variant C1QA:p.Arg27Pro (chr1-22637696-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015991.4(C1QA):c.80G>C(p.Arg27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R27G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

C1QA
NM_015991.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.318

Publications

0 publications found

Variant links:

Genes affected

C1QA (HGNC:1241): (complement C1q A chain) This gene encodes the A-chain polypeptide of serum complement subcomponent C1q, which associates with C1r and C1s to yield the first component of the serum complement system. C1q deficiency is associated with lupus erythematosus and glomerulonephritis. C1q is composed of 18 polypeptide chains which include 6 A-chains, 6 B-chains, and 6 C-chains. Each chain contains an N-terminal collagen-like region and a C-terminal C1q globular domain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

C1QA Gene-Disease associations (from GenCC):

C1Q deficiency
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

C1QA links:

ENSG00000289692 (HGNC:):

ENSG00000289692 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38542703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QA	NM_015991.4 link	c.80G>C	p.Arg27Pro	missense_variant	Exon 2 of 3	ENST00000374642.8	NP_057075.1	P02745A0A024RAG6
C1QA	NM_001347465.2 link	c.80G>C	p.Arg27Pro	missense_variant	Exon 2 of 3		NP_001334394.1	P02745A0A024RAG6
C1QA	NM_001347466.2 link	c.80G>C	p.Arg27Pro	missense_variant	Exon 2 of 3		NP_001334395.1	P02745A0A024RAG6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QA	ENST00000374642.8 link	c.80G>C	p.Arg27Pro	missense_variant	Exon 2 of 3	1	NM_015991.4	ENSP00000363773.3		P02745
ENSG00000289692	ENST00000695747.1 link	c.80G>C	p.Arg27Pro	missense_variant	Exon 2 of 5			ENSP00000512140.1		A0A8Q3SI62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.62

.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.47

N;.;N

PhyloP100

0.32

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.037

D;D;D

Sift4G

Benign

0.13

T;T;T

Polyphen

0.91

P;.;P

Vest4

0.26

MutPred

0.37

Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);

MVP

0.87

MPC

1.6

ClinPred

0.68

GERP RS

0.86

PromoterAI

0.016

Neutral

(source)

Varity_R

0.32

gMVP

0.89

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over