Variant 13-113495862-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_017905.6(TMCO3):c.281A>G(p.His94Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TMCO3
NM_017905.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.90

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]

TMCO3 links:

TMCO3 (HGNC:):

TMCO3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO3	NM_017905.6 linkuse as main transcript	c.281A>G	p.His94Arg	missense_variant	2/13	ENST00000434316.7	NP_060375.4	Q6UWJ1-1A0A024RE09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMCO3	ENST00000434316.7 linkuse as main transcript	c.281A>G	p.His94Arg	missense_variant	2/13	1	NM_017905.6	ENSP00000389399.2	Q6UWJ1-1
TMCO3	ENST00000375391.5 linkuse as main transcript	c.281A>G	p.His94Arg	missense_variant	2/8	1		ENSP00000364540.1	Q6UWJ1-3
TMCO3	ENST00000474393.5 linkuse as main transcript	c.281A>G	p.His94Arg	missense_variant	2/9	2		ENSP00000484053.1	Q6UWJ1-2
TMCO3	ENST00000473287.1 linkuse as main transcript	c.-11A>G		upstream_gene_variant		2		ENSP00000478818.1	A0A087WUP6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.281A>G (p.H94R) alteration is located in exon 2 (coding exon 1) of the TMCO3 gene. This alteration results from a A to G substitution at nucleotide position 281, causing the histidine (H) at amino acid position 94 to be replaced by an arginine (R). 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

0.19

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

T;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.0091

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.1

N;N;.

REVEL

Uncertain

0.34

Sift

Benign

0.21

T;T;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.73

P;.;P

Vest4

0.85

MutPred

0.46

Loss of methylation at K89 (P = 0.0513);Loss of methylation at K89 (P = 0.0513);Loss of methylation at K89 (P = 0.0513);

MVP

0.10

MPC

0.42

ClinPred

0.85

GERP RS

5.5

Varity_R

0.24

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.37

Position offset: -5

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over