5-140644233-C-T

Variant names:

• chr5-140644233-C-T
• rs753279
• NM_018502.5:c.1200+39C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018502.5(TMCO6):​c.1200+39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,594,126 control chromosomes in the GnomAD database, including 154,937 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (13375 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141562 hom.)
• Consequence: TMCO6 NM_018502.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.354
• Publications: 38 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 disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018502.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO6	NM_018502.5	MANE Select	c.1200+39C>T		intron	N/A	NP_060972.3
	TMCO6	NM_001300980.2		c.1218+39C>T		intron	N/A	NP_001287909.1	Q96DC7-2
	TMCO6	NM_001300982.2		c.480+39C>T		intron	N/A	NP_001287911.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO6	ENST00000394671.8	TSL:2 MANE Select	c.1200+39C>T		intron	N/A	ENSP00000378166.3	Q96DC7-1
	TMCO6	ENST00000252100.6	TSL:1	c.1218+39C>T		intron	N/A	ENSP00000252100.6	Q96DC7-2
	TMCO6	ENST00000510336.5	TSL:1	n.1361+39C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62813 AN: 151930 Hom.: 13365 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.426

GnomAD2 exomes AF: 0.434 AC: 108057 AN: 249160 AF XY: 0.436

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.509

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.442 AC: 637168 AN: 1442078 Hom.: 141562 Cov.: 29 AF XY: 0.443 AC XY: 318601 AN XY: 718594

African (AFR) AF: 0.357 AC: 11786 AN: 33020

American (AMR) AF: 0.431 AC: 19254 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 11575 AN: 26016

East Asian (EAS) AF: 0.475 AC: 18797 AN: 39604

South Asian (SAS) AF: 0.462 AC: 39669 AN: 85796

European-Finnish (FIN) AF: 0.357 AC: 19064 AN: 53400

Middle Eastern (MID) AF: 0.456 AC: 2603 AN: 5712

European-Non Finnish (NFE) AF: 0.446 AC: 488154 AN: 1094074

Other (OTH) AF: 0.440 AC: 26266 AN: 59762

GnomAD4 genome AF: 0.413 AC: 62846 AN: 152048 Hom.: 13375 Cov.: 32 AF XY: 0.410 AC XY: 30498 AN XY: 74350

African (AFR) AF: 0.350 AC: 14513 AN: 41440

American (AMR) AF: 0.428 AC: 6535 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1544 AN: 3470

East Asian (EAS) AF: 0.493 AC: 2557 AN: 5182

South Asian (SAS) AF: 0.451 AC: 2174 AN: 4824

European-Finnish (FIN) AF: 0.347 AC: 3666 AN: 10572

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30106 AN: 67966

Other (OTH) AF: 0.423 AC: 893 AN: 2110

Alfa AF: 0.438 Hom.: 30610

Bravo AF: 0.419

Asia WGS AF: 0.391 AC: 1362 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs753279; hg19: chr5-140023818; COSMIC: COSV52799296; COSMIC: COSV52799296;