5-140647863-C-T

Variant names:

• chr5-140647863-C-T
• rs139482464
• NM_006083.4:c.-46C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006083.4(IK):​c.-46C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,612,330 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (24 hom.)
• Consequence: IK NM_006083.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.296

Genes affected

IK (HGNC:5958): (IK cytokine) The protein encoded by this gene was identified by its RED repeat, a stretch of repeated arginine, glutamic acid and aspartic acid residues. The protein localizes to discrete dots within the nucleus, excluding the nucleolus. Its function is unknown. This gene maps to chromosome 5; however, a pseudogene may exist on chromosome 2. [provided by RefSeq, Jul 2008]

MIR3655 (HGNC:38960): (microRNA 3655) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-140647863-C-T is Benign according to our data. Variant chr5-140647863-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1205148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IK	NM_006083.4	c.-46C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 20	ENST00000417647.7	NP_006074.2
IK	NM_006083.4	c.-46C>T		5_prime_UTR_variant	Exon 1 of 20	ENST00000417647.7	NP_006074.2
NDUFA2	NM_002488.5	c.-280G>A		upstream_gene_variant		ENST00000252102.9	NP_002479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IK	ENST00000417647	c.-46C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 20	1	NM_006083.4	ENSP00000396301.2
IK	ENST00000417647	c.-46C>T		5_prime_UTR_variant	Exon 1 of 20	1	NM_006083.4	ENSP00000396301.2
NDUFA2	ENST00000252102.9	c.-280G>A		upstream_gene_variant		1	NM_002488.5	ENSP00000252102.5

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 512 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00338 AC: 843 AN: 249290 Hom.: 4 AF XY: 0.00339 AC XY: 459 AN XY: 135232

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00288

Gnomad NFE exome AF: 0.00548

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00463 AC: 6767 AN: 1460060 Hom.: 24 Cov.: 31 AF XY: 0.00471 AC XY: 3419 AN XY: 726432

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.00545

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74448

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00557

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00338 Hom.: 1

Bravo AF: 0.00293

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 19, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.0
DANN	Benign	0.85

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: rs139482464; hg19: chr5-140027448;