rs786204789

Positions:

• chr1-165768249-AAACC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000367881.11(TMCO1):​c.87_90del​(p.Val30ThrfsTer9) variant causes a frameshift change involving the alteration of a 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: TMCO1 ENST00000367881.11 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.96

Genes affected

TMCO1 (HGNC:18188): (transmembrane and coiled-coil domains 1) This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-165768249-AAACC-A is Pathogenic according to our data. Variant chr1-165768249-AAACC-A is described in ClinVar as [Pathogenic]. Clinvar id is 189248.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO1	NM_019026.6	c.87_90del	p.Val30ThrfsTer9	frameshift_variant	2/7	ENST00000367881.11	NP_061899.3
TMCO1	NM_001256165.1	c.51_54del	p.Val18ThrfsTer9	frameshift_variant	2/7		NP_001243094.1
TMCO1	NM_001256164.1	c.147-9_147-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001243093.1
TMCO1	NR_045818.1	n.181_184del		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCO1	ENST00000367881.11	c.87_90del	p.Val30ThrfsTer9	frameshift_variant	2/7	1	NM_019026.6	ENSP00000356856	P1

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 15, 2014

The Val81ThrfsX9 variant in TMCO1 has not been previously reported in individuals with disease or in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 81 and lead to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete TCMO1 loss-of-function is an established disease mechanism in autosomal recessive cerebrofaciothoracic dysplasia (Xin 2010, Caglayan 2013, Alanay 2014, Pehlivan 2014). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs786204789; hg19: chr1-165737486;