NM_001734.5:c.945_947delTGT

Variant names:

• chr12-7066590-ATGT-A
• rs886040974
• NM_001734.5:c.945_947delTGT

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, periodontal type 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• complement component C1s deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Ehlers-Danlos syndrome, periodontal type 1

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
C1S	NM_001734.5	c.945_947delTGT	p.Asp315_Val316delinsGlu	disruptive_inframe_deletion	Exon 8 of 12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.945_947delTGT	p.Asp315_Val316delinsGlu	disruptive_inframe_deletion	Exon 8 of 12		NP_958850.1
C1S	NM_001346850.2	c.444_446delTGT	p.Asp148_Val149delinsGlu	disruptive_inframe_deletion	Exon 7 of 11		NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.945_947delTGT	p.Asp315_Val316delinsGlu	disruptive_inframe_deletion	Exon 8 of 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

Oct 31, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 13, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1

Aug 23, 2016

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886040974; hg19: chr12-7173894;