13-113495985-G-C

Position:

• chr13-113495985-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017905.6(TMCO3):​c.404G>C​(p.Ser135Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMCO3 NM_017905.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

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]

TMCO3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO3	NM_017905.6	c.404G>C	p.Ser135Thr	missense_variant	2/13	ENST00000434316.7	NP_060375.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCO3	ENST00000434316.7	c.404G>C	p.Ser135Thr	missense_variant	2/13	1	NM_017905.6	ENSP00000389399.2
TMCO3	ENST00000375391.5	c.404G>C	p.Ser135Thr	missense_variant	2/8	1		ENSP00000364540.1
TMCO3	ENST00000474393.5	c.404G>C	p.Ser135Thr	missense_variant	2/9	2		ENSP00000484053.1
TMCO3	ENST00000473287.1	c.113G>C	p.Ser38Thr	missense_variant	1/2	2		ENSP00000478818.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.404G>C (p.S135T) alteration is located in exon 2 (coding exon 1) of the TMCO3 gene. This alteration results from a G to C substitution at nucleotide position 404, causing the serine (S) at amino acid position 135 to be replaced by a threonine (T). 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	0.27
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.92	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.094	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.91	P;.;P
Vest4		0.67
MutPred		0.26		Gain of catalytic residue at R138 (P = 0.0318);Gain of catalytic residue at R138 (P = 0.0318);Gain of catalytic residue at R138 (P = 0.0318);
MVP		0.10
MPC		0.52
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-114150300;