rs752176040

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_019026.6(TMCO1):c.139_140del(p.Ser47Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.000255 in 1,612,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

TMCO1
NM_019026.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.86

Variant links:

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]

TMCO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-165768199-ACT-A is Pathogenic according to our data. Variant chr1-165768199-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMCO1	NM_019026.6 linkuse as main transcript	c.139_140del	p.Ser47Ter	frameshift_variant	2/7	ENST00000367881.11
TMCO1	NM_001256164.1 linkuse as main transcript	c.190_191del	p.Ser64Ter	frameshift_variant	2/7
TMCO1	NM_001256165.1 linkuse as main transcript	c.103_104del	p.Ser35Ter	frameshift_variant	2/7
TMCO1	NR_045818.1 linkuse as main transcript	n.233_234del		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO1	ENST00000367881.11 linkuse as main transcript	c.139_140del	p.Ser47Ter	frameshift_variant	2/7	1	NM_019026.6	P1	Q9UM00-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251400

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000256

AC:

374

AN:

1461176

Hom.:

AF XY:

0.000246

AC XY:

179

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000317

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000250

AC:

AN:

151698

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

74080

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000348

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The c.292_293delAG (p.Ser98X) variant in TMCO1 has been reported (as c.139_140delAG: p.Ser47Ter) in the homozygous state in at least 5 individuals of Amish ancestry and in 2 additional unrelated individuals with Cerebro-facio-thoracic dysplasia, and segregated with disease in 2 affected members from 1 family (Xin 2010 PMID:20018682, Yates 2018 PMID:30556256). It has also been reported in ClinVar (Variation ID 420165). It has been identified in 0.02 (21/129086) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant creates a premature termination codon at position 98, which is predicted to lead to a truncated or absent protein. Loss of function of the TMCO1 gene is associated with autosomal recessive cerebro-facio-thoracic dysplasia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive cerebro-facio-thoracic dysplasia. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PP1, PM3_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 05, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 05, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 22, 2019	The variant was confirmed as compound heterozygous with a variant of uncertain significance (NM_019026.4: c.197C>T). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 09, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Ser98*) in the TMCO1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMCO1 are known to be pathogenic (PMID: 20018682, 23320496, 24194475, 24424126). This variant is present in population databases (rs752176040, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with craniofacial dysmorphism, skeletal anomalies, and mental retardation (PMID: 20018682). It has also been observed to segregate with disease in related individuals. This variant is also known as c.139_140delAG. ClinVar contains an entry for this variant (Variation ID: 420165). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31028937, 20018682, 31102500, 30556256) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2020

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.139_140delAG (p.S47*) alteration, located in coding exon 2 of the TMCO1 gene, results from the deletion of 2 nucleotides from position 139 to 140, causing a translational frameshift with a predicted alternate stop codon at amino acid position 47. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.139_140delAG alteration was observed in 0.0103% (29/282,676) of total alleles studied. No homozygotes were reported in gnomAD. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.139_140delAG (p.S47*) alteration in TMCO1 has been reported homozygous in multiple patients of different ethnicities with cerebrofaciothoracic dysplasia (Xin, 2010; Yates, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

TMCO1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

The TMCO1 c.292_293delAG variant is predicted to result in premature protein termination (p.Ser98*). This variant was reported the homozygous state in six individuals from an Old Order Amish family, all with craniofacial dysmorphism, skeletal anomalies, and intellectual disability; the variant was shown to segregate with disease within the family (variant described as c.139_140delAG, p.Ser47Ter in Xin et al. 2010. PubMed ID: 20018682). Further testing of undiagnosed children identified five additional Amish individuals with a similar phenotype, all homozygous for the c.292_293delAG (p.Ser98*) variant (Xin et al. 2010. PubMed ID: 20018682). This variant has also been reported in the homozygous state in three Pakistani brothers and one Scottish individual, all with craniofacial dysmorphism, skeletal anomalies, and intellectual disability (Yates et al. 2019. PubMed ID: 30556256). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-165737436-ACT-A). Other predicted loss-of-function variants in TMCO1 have been reported in affected individuals (Human Gene Mutation Database, https://www.hgmd.cf.ac.uk/). In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over