1-22639317-G-T

Position:

• chr1-22639317-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015991.4(C1QA):​c.648G>T​(p.Trp216Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,822 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: C1QA NM_015991.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1QA	NM_015991.4	c.648G>T	p.Trp216Cys	missense_variant	3/3	ENST00000374642.8	NP_057075.1
C1QA	NM_001347465.2	c.648G>T	p.Trp216Cys	missense_variant	3/3		NP_001334394.1
C1QA	NM_001347466.2	c.648G>T	p.Trp216Cys	missense_variant	3/3		NP_001334395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1QA	ENST00000374642.8	c.648G>T	p.Trp216Cys	missense_variant	3/3	1	NM_015991.4	ENSP00000363773.3
ENSG00000289692	ENST00000695747.1	c.492+156G>T		intron_variant				ENSP00000512140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.648G>T (p.W216C) alteration is located in exon 3 (coding exon 2) of the C1QA gene. This alteration results from a G to T substitution at nucleotide position 648, causing the tryptophan (W) at amino acid position 216 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	.;T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.2	M;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.63
MutPred		0.77		Gain of methylation at K219 (P = 0.1015);Gain of methylation at K219 (P = 0.1015);Gain of methylation at K219 (P = 0.1015);
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.78

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: rs34139950; hg19: chr1-22965810;