chr1-22639317-G-T

Variant names:

• chr1-22639317-G-T
• rs34139950
• NM_015991.4:c.648G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 1 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):

• systemic lupus erythematosus related to C1QA

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• C1Q deficiency

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

ENSG00000289692 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015991.4. 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
	C1QA	NM_015991.4	MANE Select	c.648G>T	p.Trp216Cys	missense	Exon 3 of 3	NP_057075.1	P02745
	C1QA	NM_001347465.2		c.648G>T	p.Trp216Cys	missense	Exon 3 of 3	NP_001334394.1	P02745
	C1QA	NM_001347466.2		c.648G>T	p.Trp216Cys	missense	Exon 3 of 3	NP_001334395.1	P02745

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QA	ENST00000374642.8	TSL:1 MANE Select	c.648G>T	p.Trp216Cys	missense	Exon 3 of 3	ENSP00000363773.3	P02745
	C1QA	ENST00000402322.2	TSL:1	c.648G>T	p.Trp216Cys	missense	Exon 3 of 3	ENSP00000385564.1	P02745
	ENSG00000289692	ENST00000695747.1		c.492+156G>T		intron	N/A	ENSP00000512140.1	A0A8Q3SI62

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

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

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111986

Other (OTH) AF: 0.0000497 AC: 3 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.9
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.77		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
Mutation Taster		=27/73	disease causing

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: rs34139950; hg19: chr1-22965810;