chr5-140642851-A-G

Variant names:

• chr5-140642851-A-G
• rs3822356
• NM_018502.5:c.690-74A>G

Variant summary

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

The NM_018502.5(TMCO6):​c.690-74A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,610,602 control chromosomes in the GnomAD database, including 42,828 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 0.19 (3375 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39453 hom.)
• Consequence: TMCO6 NM_018502.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497
• Publications: 27 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 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.690-74A>G		intron	N/A	NP_060972.3
	TMCO6	NM_001300980.2		c.690-56A>G		intron	N/A	NP_001287909.1
	TMCO6	NM_001300982.2		c.-31-74A>G		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.690-74A>G		intron	N/A	ENSP00000378166.3
	TMCO6	ENST00000252100.6	TSL:1	c.690-56A>G		intron	N/A	ENSP00000252100.6
	TMCO6	ENST00000510336.5	TSL:1	n.851-74A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29352 AN: 151984 Hom.: 3362 Cov.: 32

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.195

GnomAD4 exome AF: 0.229 AC: 334526 AN: 1458500 Hom.: 39453 Cov.: 32 AF XY: 0.231 AC XY: 167132 AN XY: 725044

African (AFR) AF: 0.0750 AC: 2507 AN: 33436

American (AMR) AF: 0.222 AC: 9888 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4977 AN: 25986

East Asian (EAS) AF: 0.283 AC: 11233 AN: 39632

South Asian (SAS) AF: 0.248 AC: 21330 AN: 86100

European-Finnish (FIN) AF: 0.286 AC: 15252 AN: 53314

Middle Eastern (MID) AF: 0.175 AC: 1006 AN: 5740

European-Non Finnish (NFE) AF: 0.230 AC: 254638 AN: 1109410

Other (OTH) AF: 0.227 AC: 13695 AN: 60266

GnomAD4 genome AF: 0.193 AC: 29374 AN: 152102 Hom.: 3375 Cov.: 32 AF XY: 0.195 AC XY: 14508 AN XY: 74342

African (AFR) AF: 0.0820 AC: 3404 AN: 41498

American (AMR) AF: 0.213 AC: 3255 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3472

East Asian (EAS) AF: 0.295 AC: 1525 AN: 5172

South Asian (SAS) AF: 0.252 AC: 1213 AN: 4822

European-Finnish (FIN) AF: 0.286 AC: 3015 AN: 10560

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15770 AN: 67972

Other (OTH) AF: 0.200 AC: 421 AN: 2108

Alfa AF: 0.223 Hom.: 3915

Bravo AF: 0.181

Asia WGS AF: 0.310 AC: 1075 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-0.50
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: rs3822356; hg19: chr5-140022436; COSMIC: COSV52799684; COSMIC: COSV52799684;