5-140642374-G-C

Position:

• chr5-140642374-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.558G>C​(p.Gln186His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TMCO6 NM_018502.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.895

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=0.25664818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO6	NM_018502.5	c.558G>C	p.Gln186His	missense_variant	5/12	ENST00000394671.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO6	ENST00000394671.8	c.558G>C	p.Gln186His	missense_variant	5/12	2	NM_018502.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461402 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

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

Oct 17, 2023

The c.558G>C (p.Q186H) alteration is located in exon 5 (coding exon 5) of the TMCO6 gene. This alteration results from a G to C substitution at nucleotide position 558, causing the glutamine (Q) at amino acid position 186 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.25
MutPred		0.35		Gain of catalytic residue at R184 (P = 0.1066);Gain of catalytic residue at R184 (P = 0.1066);
MVP		0.65
MPC		0.19
ClinPred		0.57	D
GERP RS		4.9
Varity_R		0.098
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-140021959;