rs17887074

chr1-22637683-G-Achr1-22637683-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015991.4(C1QA):c.67G>A(p.Glu23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,614,002 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E23Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (20 hom.)
• Consequence: C1QA NM_015991.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.525

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006098807).
• BP6: Variant 1-22637683-G-A is Benign according to our data. Variant chr1-22637683-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 522247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-22637683-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0032 (487/152264) while in subpopulation NFE AF= 0.00406 (276/68010). AF 95% confidence interval is 0.00366. There are 5 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1QA	NM_015991.4	c.67G>A	p.Glu23Lys	missense_variant	2/3	ENST00000374642.8
C1QA	NM_001347465.2	c.67G>A	p.Glu23Lys	missense_variant	2/3
C1QA	NM_001347466.2	c.67G>A	p.Glu23Lys	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QA	ENST00000374642.8	c.67G>A	p.Glu23Lys	missense_variant	2/3	1	NM_015991.4	P1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152146 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00316 AC: 794 AN: 250948 Hom.: 7 AF XY: 0.00313 AC XY: 425 AN XY: 135676

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.00316

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00321 AC: 4690 AN: 1461738 Hom.: 20 Cov.: 32 AF XY: 0.00317 AC XY: 2305 AN XY: 727158

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00257

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.00317

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00320 AC: 487 AN: 152264 Hom.: 5 Cov.: 33 AF XY: 0.00364 AC XY: 271 AN XY: 74450

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00312 Hom.: 3

Bravo AF: 0.00163

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	C1QA: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

C1Q deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

C1QA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	12
Dann	Benign	0.88
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.073	N
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.88	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.055	T;D;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.38	B;.;B
Vest4		0.27
MVP		0.63
MPC		0.71
ClinPred		0.020	T
GERP RS		-4.5
Varity_R		0.045
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17887074; hg19: chr1-22964176;