rs886040974

Positions:

• chr12-7066590-ATGT-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_001734.5(C1S):​c.945_947delTGT​(p.Asp315_Val316delinsGlu) variant causes a disruptive inframe deletion 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1S NM_001734.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.618

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]

C1S (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001734.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-7066590-ATGT-A is Pathogenic according to our data. Variant chr12-7066590-ATGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 267348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1S	NM_001734.5	c.945_947delTGT	p.Asp315_Val316delinsGlu	disruptive_inframe_deletion	8/12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.945_947delTGT	p.Asp315_Val316delinsGlu	disruptive_inframe_deletion	8/12		NP_958850.1
C1S	NM_001346850.2	c.444_446delTGT	p.Asp148_Val149delinsGlu	disruptive_inframe_deletion	7/11		NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.945_947delTGT	p.Asp315_Val316delinsGlu	disruptive_inframe_deletion	8/12	1	NM_001734.5	ENSP00000354057.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Oct 13, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 31, 2016	- -

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, Medical University Innsbruck

Aug 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs886040974; hg19: chr12-7173894;