13-113495689-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017905.6(TMCO3):​c.108C>A​(p.His36Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,612,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TMCO3
NM_017905.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.892
Variant links:
Genes affected
TMCO3 (HGNC:20329): (transmembrane and coiled-coil domains 3) This gene encodes a member of the monovalent cation:proton antiporter 2 (CPA2) family of transporter proteins. Members of this family typically couple the export of monovalent cations, such as potassium or sodium, to the import of protons across cellular membranes. Mutations in this gene have been identified in patients with a rare inherited vision defect, cornea guttata with anterior polar cataract. [provided by RefSeq, Mar 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.088484734).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMCO3NM_017905.6 linkc.108C>A p.His36Gln missense_variant Exon 2 of 13 ENST00000434316.7 NP_060375.4 Q6UWJ1-1A0A024RE09

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMCO3ENST00000434316.7 linkc.108C>A p.His36Gln missense_variant Exon 2 of 13 1 NM_017905.6 ENSP00000389399.2 Q6UWJ1-1
TMCO3ENST00000375391.5 linkc.108C>A p.His36Gln missense_variant Exon 2 of 8 1 ENSP00000364540.1 Q6UWJ1-3
TMCO3ENST00000474393.5 linkc.108C>A p.His36Gln missense_variant Exon 2 of 9 2 ENSP00000484053.1 Q6UWJ1-2
TMCO3ENST00000473287.1 linkc.-184C>A upstream_gene_variant 2 ENSP00000478818.1 A0A087WUP6

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152150
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000479
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250030
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135388
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1460070
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
726022
show subpopulations
Gnomad4 AFR exome
AF:
0.000448
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152268
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000131
Hom.:
0
Bravo
AF:
0.000151
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.108C>A (p.H36Q) alteration is located in exon 2 (coding exon 1) of the TMCO3 gene. This alteration results from a C to A substitution at nucleotide position 108, causing the histidine (H) at amino acid position 36 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
17
DANN
Benign
0.80
DEOGEN2
Benign
0.0097
T;.;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.67
T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.088
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L;L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.78
N;N;.
REVEL
Benign
0.077
Sift
Uncertain
0.011
D;D;.
Sift4G
Uncertain
0.021
D;D;D
Polyphen
0.0020
B;.;B
Vest4
0.47
MutPred
0.40
Gain of catalytic residue at V41 (P = 0);Gain of catalytic residue at V41 (P = 0);Gain of catalytic residue at V41 (P = 0);
MVP
0.081
MPC
0.25
ClinPred
0.074
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.12
gMVP
0.39

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.

Other links and lift over

dbSNP: rs202111246; hg19: chr13-114150004; API