Genetic Variant TMCO1:p.Val114Leu (chr1-165743295-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_019026.6(TMCO1):c.340G>T(p.Val114Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

TMCO1
NM_019026.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

cerebrofaciothoracic dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Laboratory for Molecular Medicine, Orphanet
craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

TMCO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019026.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMCO1	NM_019026.6	MANE Select	c.340G>T	p.Val114Leu	missense	Exon 6 of 7	NP_061899.3	Q9UM00-1
TMCO1	NM_001256164.1		c.391G>T	p.Val131Leu	missense	Exon 6 of 7	NP_001243093.1	B7Z591
TMCO1	NM_001256165.1		c.304G>T	p.Val102Leu	missense	Exon 6 of 7	NP_001243094.1	B7Z591

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMCO1	ENST00000367881.11	TSL:1 MANE Select	c.340G>T	p.Val114Leu	missense	Exon 6 of 7	ENSP00000356856.6	Q9UM00-1
TMCO1	ENST00000612311.4	TSL:1	c.493G>T	p.Val165Leu	missense	Exon 6 of 7	ENSP00000480514.1	Q9UM00-3
TMCO1	ENST00000868463.1		c.463G>T	p.Val155Leu	missense	Exon 7 of 8	ENSP00000538522.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151138

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73732

African (AFR)

AF:

0.00

AC:

AN:

41044

American (AMR)

AF:

0.00

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2078

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.2

PhyloP100

7.5

PrimateAI

Uncertain

0.74

REVEL

Uncertain

0.49

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.84

MutPred

0.72

Loss of sheet (P = 0.0181)

MVP

0.15

MPC

1.2

ClinPred

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.88

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over