chr1-22637741-G-A

Position:

• chr1-22637741-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_015991.4(C1QA):​c.125G>A​(p.Arg42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000877 in 1,606,844 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (2 hom.)
• Consequence: C1QA NM_015991.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.713

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07010692).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000866 (126/1454596) while in subpopulation MID AF= 0.00191 (10/5226). AF 95% confidence interval is 0.00104. There are 2 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1QA	NM_015991.4	c.125G>A	p.Arg42Gln	missense_variant	2/3	ENST00000374642.8
C1QA	NM_001347465.2	c.125G>A	p.Arg42Gln	missense_variant	2/3
C1QA	NM_001347466.2	c.125G>A	p.Arg42Gln	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QA	ENST00000374642.8	c.125G>A	p.Arg42Gln	missense_variant	2/3	1	NM_015991.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000116 AC: 27 AN: 233266 Hom.: 0 AF XY: 0.000135 AC XY: 17 AN XY: 126328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000247

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0000582

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.0000496

Gnomad NFE exome AF: 0.0000955

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000866 AC: 126 AN: 1454596 Hom.: 2 Cov.: 31 AF XY: 0.0000954 AC XY: 69 AN XY: 722988

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000208

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000376

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000577

Gnomad4 OTH exome AF: 0.0000999

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74436

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 42 of the C1QA protein (p.Arg42Gln). This variant is present in population databases (rs201693493, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with C1QA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1057187). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.81	.;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.17	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.093	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.099
MVP		0.97
MPC		0.63
ClinPred		0.044	T
GERP RS		4.0
Varity_R		0.032
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201693493; hg19: chr1-22964234;