rs11744596

Variant names:

• chr5-69223464-T-G
• rs11744596
• NM_033281.6:c.43-2874T>G

Variant summary

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

The NM_033281.6(KGD4):​c.43-2874T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 151,642 control chromosomes in the GnomAD database, including 15,250 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 0.45 (15250 hom., cov: 31)
• Consequence: KGD4 NM_033281.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• Publications: 11 publications found

Genes affected

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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KGD4	NM_033281.6	c.43-2874T>G		intron_variant	Intron 1 of 3	ENST00000256441.5	NP_150597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KGD4	ENST00000256441.5	c.43-2874T>G		intron_variant	Intron 1 of 3	1	NM_033281.6	ENSP00000256441.4

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67705 AN: 151522 Hom.: 15234 Cov.: 31

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.428

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

GnomAD4 genome AF: 0.447 AC: 67753 AN: 151642 Hom.: 15250 Cov.: 31 AF XY: 0.450 AC XY: 33292 AN XY: 74018

African (AFR) AF: 0.499 AC: 20664 AN: 41386

American (AMR) AF: 0.457 AC: 6944 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1270 AN: 3458

East Asian (EAS) AF: 0.458 AC: 2361 AN: 5156

South Asian (SAS) AF: 0.560 AC: 2695 AN: 4814

European-Finnish (FIN) AF: 0.392 AC: 4122 AN: 10522

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28082 AN: 67806

Other (OTH) AF: 0.429 AC: 904 AN: 2106

Alfa AF: 0.428 Hom.: 7489

Bravo AF: 0.449

Asia WGS AF: 0.529 AC: 1840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		2.0
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: rs11744596; hg19: chr5-68519291; COSMIC: COSV56507749;