12-7062477-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001734.5(C1S):c.8G>T(p.Cys3Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: C1S NM_001734.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.755

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16561264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1S	NM_001734.5	c.8G>T	p.Cys3Phe	missense_variant, splice_region_variant	3/12	ENST00000360817.10
C1S	NM_201442.4	c.8G>T	p.Cys3Phe	missense_variant, splice_region_variant	3/12
C1S	NM_001346850.2	c.-288-413G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1S	ENST00000360817.10	c.8G>T	p.Cys3Phe	missense_variant, splice_region_variant	3/12	1	NM_001734.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 3 of the C1S protein (p.Cys3Phe). This variant has not been reported in the literature in individuals affected with C1S-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	8.8
Dann	Benign	0.85
DEOGEN2	Benign	0.056	T;T;T;.;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.4	L;L;L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.13	T;T;T;T;T;T
Sift4G	Benign	0.80	T;T;T;T;T;T
Polyphen		0.017	B;B;B;.;.;.
Vest4		0.49
MutPred		0.56		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.71
MPC		0.33
ClinPred		0.017	T
GERP RS		1.8
Varity_R		0.070
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7169781;