1-22637695-C-T

Variant names:

• chr1-22637695-C-T
• rs952339666
• NM_015991.4:c.79C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_015991.4(C1QA):​c.79C>T​(p.Arg27*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: C1QA NM_015991.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.288

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]

ENSG00000289692 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-22637695-C-T is Pathogenic according to our data. Variant chr1-22637695-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1332787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QA	NM_015991.4	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 3	ENST00000374642.8	NP_057075.1
C1QA	NM_001347465.2	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 3		NP_001334394.1
C1QA	NM_001347466.2	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 3		NP_001334395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QA	ENST00000374642.8	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 3	1	NM_015991.4	ENSP00000363773.3
ENSG00000289692	ENST00000695747.1	c.79C>T	p.Arg27*	stop_gained	Exon 2 of 5			ENSP00000512140.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250544 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135478

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 SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461596 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1332787). This variant has not been reported in the literature in individuals affected with C1QA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg27*) in the C1QA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C1QA are known to be pathogenic (PMID: 9590289, 21654842, 22472776). -

C1Q deficiency Pathogenic:1

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.76	D
Vest4		0.84
ClinPred		0.96	D
GERP RS		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs952339666; hg19: chr1-22964188;