1-22637683-G-A

Position:

chr1-22637683-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000374642.8(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
ENST00000374642.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.525

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
C1QA	NM_015991.4 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	2/3	ENST00000374642.8	NP_057075.1
C1QA	NM_001347465.2 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	2/3		NP_001334394.1
C1QA	NM_001347466.2 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	2/3		NP_001334395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1QA	ENST00000374642.8 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	2/3	1	NM_015991.4	ENSP00000363773	P1

Frequencies

GnomAD3 genomes

AF:

0.00320

AC:

487

AN:

152146

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00313

AC XY:

425

AN XY:

135676

show subpopulations

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.:

Cov.:

AF XY:

0.00317

AC XY:

2305

AN XY:

727158

show subpopulations

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.:

Cov.:

AF XY:

0.00364

AC XY:

271

AN XY:

74450

show subpopulations

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.:

Bravo

AF:

0.00163

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00263

AC:

319

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.29

CADD

Benign

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

LIST_S2

Benign

0.75

.;T;T

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.88

L;.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over