chr5-140639819-G-A

Variant names:

• chr5-140639819-G-A
• NM_018502.5:c.166G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018502.5(TMCO6):​c.166G>A​(p.Gly56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMCO6 NM_018502.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 0 publications found

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]

NDUFA2 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• cystic leukoencephalopathy without megalencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07521647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCO6	NM_018502.5	c.166G>A	p.Gly56Arg	missense_variant	Exon 2 of 12	ENST00000394671.8	NP_060972.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO6	ENST00000394671.8	c.166G>A	p.Gly56Arg	missense_variant	Exon 2 of 12	2	NM_018502.5	ENSP00000378166.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457376 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724402

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 43990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 84938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110614

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166G>A (p.G56R) alteration is located in exon 2 (coding exon 2) of the TMCO6 gene. This alteration results from a G to A substitution at nucleotide position 166, causing the glycine (G) at amino acid position 56 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	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.0069	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;M
PhyloP100		3.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.068
Sift	Benign	0.49	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.59	P;P
Vest4		0.081
MutPred		0.29		Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP		0.32
MPC		0.43
ClinPred		0.21	T
GERP RS		2.4
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.22
Mutation Taster		=285/15	polymorphism

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

Other links and lift over

hg19: chr5-140019404;