2-27847066-C-A

Variant names:

• chr2-27847066-C-A
• rs780321086
• NM_022128.3:c.325G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022128.3(RBKS):​c.325G>T​(p.Ala109Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000747 in 1,606,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: RBKS NM_022128.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022128.3. 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
	RBKS	NM_022128.3	MANE Select	c.325G>T	p.Ala109Ser	missense	Exon 4 of 8	NP_071411.1	Q9H477-1
	RBKS	NM_001287580.2		c.124G>T	p.Ala42Ser	missense	Exon 5 of 9	NP_001274509.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBKS	ENST00000302188.8	TSL:1 MANE Select	c.325G>T	p.Ala109Ser	missense	Exon 4 of 8	ENSP00000306817.3	Q9H477-1
	RBKS	ENST00000449378.1	TSL:1	n.*1252G>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000413789.1	E7EQ18
	RBKS	ENST00000449378.1	TSL:1	n.*1252G>T		3_prime_UTR	Exon 5 of 9	ENSP00000413789.1	E7EQ18

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1454786 Hom.: 0 Cov.: 27 AF XY: 0.00000690 AC XY: 5 AN XY: 724202

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00000995 AC: 11 AN: 1106026

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.64
Sift	Benign	0.036	D
Sift4G	Uncertain	0.043	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.84		Gain of glycosylation at A109 (P = 0.0482)
MVP		0.78
MPC		0.25
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.59
gMVP		0.83
Mutation Taster		=57/43	polymorphism

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: rs780321086; hg19: chr2-28069933;