12-7062516-A-T

Position:

• chr12-7062516-A-T

Variant summary

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

The NM_001734.5(C1S):​c.47A>T​(p.Glu16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E16E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1S NM_001734.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1S	NM_001734.5	c.47A>T	p.Glu16Val	missense_variant	3/12	ENST00000360817.10
C1S	NM_201442.4	c.47A>T	p.Glu16Val	missense_variant	3/12
C1S	NM_001346850.2	c.-288-374A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1S	ENST00000360817.10	c.47A>T	p.Glu16Val	missense_variant	3/12	1	NM_001734.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.47A>T (p.E16V) alteration is located in exon 3 (coding exon 2) of the C1S gene. This alteration results from a A to T substitution at nucleotide position 47, causing the glutamic acid (E) at amino acid position 16 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;T;T;.;T;T
Eigen	Benign	-0.023
Eigen_PC	Benign	0.0046
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	.;.;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.3	L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.32	N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.33	T;T;T;D;T;T
Sift4G	Benign	0.069	T;T;T;T;T;T
Polyphen		0.80	P;P;P;.;.;.
Vest4		0.66
MutPred		0.63		Gain of glycosylation at T18 (P = 0.112);Gain of glycosylation at T18 (P = 0.112);Gain of glycosylation at T18 (P = 0.112);Gain of glycosylation at T18 (P = 0.112);Gain of glycosylation at T18 (P = 0.112);Gain of glycosylation at T18 (P = 0.112);
MVP		0.91
MPC		0.65
ClinPred		0.65	D
GERP RS		2.9
Varity_R		0.25
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr12-7169820;