12-7070184-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_001734.5(C1S):​c.1600C>T​(p.Arg534Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,016 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R534Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

C1S
NM_001734.5 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.00
Variant links:
Genes affected
C1S (HGNC:1247): (complement C1s) This gene encodes a serine protease, which is a major constituent of the human complement subcomponent C1. C1s associates with two other complement components C1r and C1q in order to yield the first component of the serum complement system. Defects in this gene are the cause of selective C1s deficiency. [provided by RefSeq, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.752
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00021 (32/152200) while in subpopulation NFE AF= 0.000426 (29/68038). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C1SNM_001734.5 linkc.1600C>T p.Arg534Trp missense_variant Exon 12 of 12 ENST00000360817.10 NP_001725.1 P09871
C1SNM_201442.4 linkc.1600C>T p.Arg534Trp missense_variant Exon 12 of 12 NP_958850.1 P09871
C1SNM_001346850.2 linkc.1099C>T p.Arg367Trp missense_variant Exon 11 of 11 NP_001333779.1 P09871F8WCZ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C1SENST00000360817.10 linkc.1600C>T p.Arg534Trp missense_variant Exon 12 of 12 1 NM_001734.5 ENSP00000354057.5 P09871

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251114
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135726
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000247
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000108
AC:
158
AN:
1461816
Hom.:
0
Cov.:
32
AF XY:
0.000114
AC XY:
83
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000131
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000426
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000353
Hom.:
0
Bravo
AF:
0.000174
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.000273
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 534 of the C1S protein (p.Arg534Trp). This variant is present in population databases (rs121909582, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with C1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 17068). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt C1S protein function with a positive predictive value of 80%. 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. -

Oct 20, 2020
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Dec 06, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: C1S c.1600C>T (p.Arg534Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251114 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in C1S causing Complement component C1s deficiency, allowing no conclusion about variant significance. c.1600C>T has been reported in the literature in an individual affected with an ALPS-like phenotype without strong evidence of causality (Grossi_2021). This report does not provide unequivocal conclusions about association of the variant with Complement component C1s deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34573280). ClinVar contains an entry for this variant (Variation ID: 17068). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Complement component C1s deficiency;C4310681:Ehlers-Danlos syndrome, periodontal type 2 Uncertain:1
May 16, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.67
D;D;D;.;D
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
.;.;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D
MetaSVM
Uncertain
0.075
D
MutationAssessor
Pathogenic
3.3
M;M;M;.;.
PrimateAI
Benign
0.23
T
PROVEAN
Pathogenic
-4.5
D;D;D;.;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0020
D;D;D;.;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.38
MVP
0.78
MPC
0.70
ClinPred
0.76
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.86
gMVP
0.83

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs121909582; hg19: chr12-7177488; API