dbSNP rs17887074: C1QA:p.Glu23Lys (chr1-22637683-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 16/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.525

Publications

9 publications found

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 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

C1QA links:

ENSG00000289692 (HGNC:):

ENSG00000289692 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 522247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1QA	NM_015991.4	MANE Select	c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	NP_057075.1	P02745
C1QA	NM_001347465.2		c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	NP_001334394.1	P02745
C1QA	NM_001347466.2		c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	NP_001334395.1	P02745

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1QA	ENST00000374642.8	TSL:1 MANE Select	c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	ENSP00000363773.3	P02745
C1QA	ENST00000402322.2	TSL:1	c.67G>A	p.Glu23Lys	missense	Exon 2 of 3	ENSP00000385564.1	P02745
ENSG00000289692	ENST00000695747.1		c.67G>A	p.Glu23Lys	missense	Exon 2 of 5	ENSP00000512140.1	A0A8Q3SI62

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

GnomAD2 exomes

AF:

0.00316

AC:

794

AN:

250948

AF XY:

0.00313

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 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

African (AFR)

AF:

0.000418

AC:

AN:

33478

American (AMR)

AF:

0.000425

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00257

AC:

222

AN:

86234

European-Finnish (FIN)

AF:

0.0127

AC:

677

AN:

53418

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00317

AC:

3526

AN:

1111952

Other (OTH)

AF:

0.00232

AC:

140

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

299

598

896

1195

1494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00320

AC:

487

AN:

152264

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

271

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41542

American (AMR)

AF:

0.000523

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00228

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00406

AC:

276

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00297

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

C1Q deficiency (2)

C1QA-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.12

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.88

PhyloP100

-0.53

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

REVEL

Benign

0.26

Sift

Benign

0.055

Sift4G

Benign

0.30

Polyphen

0.38

Vest4

0.27

MVP

0.63

MPC

0.71

ClinPred

0.020

GERP RS

-4.5

PromoterAI

0.011

Neutral

(source)

Varity_R

0.045

gMVP

0.72

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over