5-140642627-G-C

Variant names:

• chr5-140642627-G-C
• rs201116062
• NM_018502.5:c.645G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018502.5(TMCO6):​c.645G>C​(p.Leu215Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: TMCO6 NM_018502.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3347721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCO6	NM_018502.5	c.645G>C	p.Leu215Phe	missense_variant	Exon 6 of 12	ENST00000394671.8	NP_060972.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO6	ENST00000394671.8	c.645G>C	p.Leu215Phe	missense_variant	Exon 6 of 12	2	NM_018502.5	ENSP00000378166.3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000373 AC: 93 AN: 249568 Hom.: 0 AF XY: 0.000362 AC XY: 49 AN XY: 135400

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000655 AC: 957 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000630 AC XY: 458 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000799

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74492

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000626 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000726 AC: 6

ExAC AF: 0.000372 AC: 45

EpiCase AF: 0.000600

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.645G>C (p.L215F) alteration is located in exon 6 (coding exon 6) of the TMCO6 gene. This alteration results from a G to C substitution at nucleotide position 645, causing the leucine (L) at amino acid position 215 to be replaced by a phenylalanine (F). 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	0.18
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.38
Sift	Benign	0.080	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.93	P;P
Vest4		0.63
MutPred		0.55		Gain of catalytic residue at L215 (P = 0.0797);Gain of catalytic residue at L215 (P = 0.0797);
MVP		0.79
MPC		0.81
ClinPred		0.26	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201116062; hg19: chr5-140022212;