rs4464229

Positions:

• chr2-27815213-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022128.3(RBKS):​c.795+12354G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 151,174 control chromosomes in the GnomAD database, including 6,352 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 0.27 (6352 hom., cov: 30)
• Consequence: RBKS NM_022128.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627

Genes affected

RBKS (HGNC:30325): (ribokinase) This gene encodes a member of the carbohydrate kinase PfkB family. The encoded protein phosphorylates ribose to form ribose-5-phosphate in the presence of ATP and magnesium as a first step in ribose metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

MRPL33 (HGNC:14487): (mitochondrial ribosomal protein L33) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist 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 39S subunit protein. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBKS	NM_022128.3	c.795+12354G>A		intron_variant		ENST00000302188.8	NP_071411.1
RBKS	NM_001287580.2	c.594+12354G>A		intron_variant			NP_001274509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBKS	ENST00000302188.8	c.795+12354G>A		intron_variant		1	NM_022128.3	ENSP00000306817	P1
RBKS	ENST00000449378.1	c.*1722+12354G>A		intron_variant, NMD_transcript_variant		1		ENSP00000413789
RBKS	ENST00000458185.1	c.377-5168G>A		intron_variant		3		ENSP00000393558
MRPL33	ENST00000448427.1	c.164+32519C>T		intron_variant, NMD_transcript_variant		4		ENSP00000407385

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40492 AN: 151054 Hom.: 6333 Cov.: 30

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.268 AC: 40564 AN: 151174 Hom.: 6352 Cov.: 30 AF XY: 0.278 AC XY: 20484 AN XY: 73776

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.252

Alfa AF: 0.205 Hom.: 3862

Bravo AF: 0.286

Asia WGS AF: 0.447 AC: 1550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.34
DANN	Benign	0.076

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: rs4464229; hg19: chr2-28038080;