rs121909581

Variant names:

• chr1-22639291-C-T
• rs121909581
• NM_015991.4:c.622C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_015991.4(C1QA):​c.622C>T​(p.Gln208*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,461,798 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: C1QA NM_015991.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.443
• Publications: 13 publications found

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

ENSG00000289692 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.157 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 1-22639291-C-T is Pathogenic according to our data. Variant chr1-22639291-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17073.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.622C>T	p.Gln208*	stop_gained	Exon 3 of 3	ENST00000374642.8	NP_057075.1
C1QA	NM_001347465.2	c.622C>T	p.Gln208*	stop_gained	Exon 3 of 3		NP_001334394.1
C1QA	NM_001347466.2	c.622C>T	p.Gln208*	stop_gained	Exon 3 of 3		NP_001334395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QA	ENST00000374642.8	c.622C>T	p.Gln208*	stop_gained	Exon 3 of 3	1	NM_015991.4	ENSP00000363773.3
ENSG00000289692	ENST00000695747.1	c.492+130C>T		intron_variant	Intron 3 of 4			ENSP00000512140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251244 AF XY: 0.0000663

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: 0.0000253 AC: 37 AN: 1461798 Hom.: 1 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.000143 Hom.: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

C1Q deficiency Pathogenic:2

Jul 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln208*) in the C1QA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the C1QA protein. This variant is present in population databases (rs121909581, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with C1q deficiency (PMID: 7594474, 8840296, 9225968, 21654842, 26563161, 29739689, 30008451). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln186*. ClinVar contains an entry for this variant (Variation ID: 17073). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Benign	0.97
Eigen	Benign	0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.16	N
PhyloP100		0.44
Vest4		0.50
GERP RS		2.7
Mutation Taster		=26/174	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909581; hg19: chr1-22965784;