GeneBe

1-165743263-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_019026.6(TMCO1):​c.372C>A​(p.Tyr124*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,611,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TMCO1
NM_019026.6 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.781

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 1-165743263-G-T is Pathogenic according to our data. Variant chr1-165743263-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521850.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMCO1NM_019026.6 linkc.372C>A p.Tyr124* stop_gained Exon 6 of 7 ENST00000367881.11 NP_061899.3 Q9UM00-1
TMCO1NM_001256164.1 linkc.423C>A p.Tyr141* stop_gained Exon 6 of 7 NP_001243093.1 B7Z591
TMCO1NM_001256165.1 linkc.336C>A p.Tyr112* stop_gained Exon 6 of 7 NP_001243094.1 B7Z591
TMCO1NR_045818.1 linkn.466C>A non_coding_transcript_exon_variant Exon 6 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMCO1ENST00000367881.11 linkc.372C>A p.Tyr124* stop_gained Exon 6 of 7 1 NM_019026.6 ENSP00000356856.6 Q9UM00-1

Frequencies

GnomAD3 genomes
AF:
0.00000661
AC:
1
AN:
151244
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000659
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
AF:
0.00000685
AC:
10
AN:
1460374
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726494
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33440
American (AMR)
AF:
0.00
AC:
0
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26068
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39610
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86228
European-Finnish (FIN)
AF:
0.0000188
AC:
1
AN:
53254
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1111016
Other (OTH)
AF:
0.00
AC:
0
AN:
60294
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000661
AC:
1
AN:
151244
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73756
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41134
American (AMR)
AF:
0.0000659
AC:
1
AN:
15166
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5154
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4782
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10300
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67936
Other (OTH)
AF:
0.00
AC:
0
AN:
2080
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Jun 06, 2017
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.92
D
PhyloP100
0.78
Vest4
0.46
GERP RS
3.4
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1553249737; hg19: chr1-165712500; API