5-140641716-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018502.5(TMCO6):c.250G>C(p.Glu84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMCO6 NM_018502.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

Genes affected

TMCO6 (HGNC:28814): (transmembrane and coiled-coil domains 6) Predicted to enable nuclear import signal receptor activity. Predicted to be involved in protein import into nucleus. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

NDUFA2 (HGNC:7685): (NADH:ubiquinone oxidoreductase subunit A2) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

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=0.08314678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO6	NM_018502.5	c.250G>C	p.Glu84Gln	missense_variant	3/12	ENST00000394671.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO6	ENST00000394671.8	c.250G>C	p.Glu84Gln	missense_variant	3/12	2	NM_018502.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 02, 2021

The c.250G>C (p.E84Q) alteration is located in exon 3 (coding exon 3) of the TMCO6 gene. This alteration results from a G to C substitution at nucleotide position 250, causing the glutamic acid (E) at amino acid position 84 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	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0069	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.98	D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.039
Sift	Benign	0.18	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0020	B;B
Vest4		0.17
MutPred		0.33		Gain of MoRF binding (P = 0.0168);Gain of MoRF binding (P = 0.0168);
MVP		0.33
MPC		0.21
ClinPred		0.12	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.18

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: chr5-140021301;