rs6450023

Variant names:

• chr5-69230236-T-C
• rs6450023
• ENST00000835232.1:n.214-1218A>G

Variant summary

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

The ENST00000835232.1(ENSG00000308592):​n.214-1218A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 151,956 control chromosomes in the GnomAD database, including 10,341 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 0.33 (10341 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000308592 ENST00000835232.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308
• Publications: 7 publications found

Genes affected

ENSG00000308592 (HGNC:):

KGD4 (HGNC:16631): (alpha-ketoglutarate dehydrogenase subunit 4) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. The mitochondrial ribosome (mitoribosome) consists of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. Pseudogenes corresponding to this gene are found on chromosomes 3p, 4q, 8p, 11q, 12q, and 20p. [provided by RefSeq, Jul 2008]

KGD4 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000835232.1. 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
	KGD4	NM_033281.6	MANE Select	c.*1011T>C		downstream_gene	N/A	NP_150597.1	P82909

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000308592	ENST00000835232.1		n.214-1218A>G		intron	N/A
	ENSG00000308592	ENST00000835233.1		n.160-1926A>G		intron	N/A
	KGD4	ENST00000256441.5	TSL:1 MANE Select	c.*1011T>C		downstream_gene	N/A	ENSP00000256441.4	P82909

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49401 AN: 151838 Hom.: 10308 Cov.: 31

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.297

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.326 AC: 49482 AN: 151956 Hom.: 10341 Cov.: 31 AF XY: 0.326 AC XY: 24236 AN XY: 74244

African (AFR) AF: 0.591 AC: 24477 AN: 41422

American (AMR) AF: 0.336 AC: 5123 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 894 AN: 3470

East Asian (EAS) AF: 0.116 AC: 599 AN: 5178

South Asian (SAS) AF: 0.280 AC: 1350 AN: 4816

European-Finnish (FIN) AF: 0.230 AC: 2428 AN: 10536

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.203 AC: 13803 AN: 67966

Other (OTH) AF: 0.295 AC: 622 AN: 2112

Alfa AF: 0.257 Hom.: 15547

Bravo AF: 0.342

Asia WGS AF: 0.246 AC: 861 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		-0.31

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6450023;

hg19: chr5-68526063;