13-113495689-C-A

Variant names:

• chr13-113495689-C-A
• rs202111246
• NM_017905.6:c.108C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892

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]

ACMG classification

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
TMCO3	NM_017905.6	c.108C>A	p.His36Gln	missense_variant	Exon 2 of 13	ENST00000434316.7	NP_060375.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO3	ENST00000434316.7	c.108C>A	p.His36Gln	missense_variant	Exon 2 of 13	1	NM_017905.6	ENSP00000389399.2
TMCO3	ENST00000375391.5	c.108C>A	p.His36Gln	missense_variant	Exon 2 of 8	1		ENSP00000364540.1
TMCO3	ENST00000474393.5	c.108C>A	p.His36Gln	missense_variant	Exon 2 of 9	2		ENSP00000484053.1
TMCO3	ENST00000473287.1	c.-184C>A		upstream_gene_variant		2		ENSP00000478818.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152150 Hom.: 0 Cov.: 33

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

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

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

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

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

Other links and lift over

dbSNP: rs202111246; hg19: chr13-114150004;