rs3822356

Positions:

• chr5-140642851-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO6	NM_018502.5	c.690-74A>G		intron_variant		ENST00000394671.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO6	ENST00000394671.8	c.690-74A>G		intron_variant		2	NM_018502.5	A1

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

Gnomad4 AFR exome AF: 0.0750

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.227

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

Gnomad4 AFR AF: 0.0820

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.232

Gnomad4 OTH AF: 0.200

Alfa AF: 0.224 Hom.: 3739

Bravo AF: 0.181

Asia WGS AF: 0.310 AC: 1075 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs3822356; hg19: chr5-140022436; COSMIC: COSV52799684; COSMIC: COSV52799684;