2-27858560-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022128.3(RBKS):c.101G>A(p.Arg34His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: RBKS NM_022128.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBKS	NM_022128.3	c.101G>A	p.Arg34His	missense_variant	2/8	ENST00000302188.8
RBKS	NM_001287580.2	c.-101G>A		5_prime_UTR_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBKS	ENST00000302188.8	c.101G>A	p.Arg34His	missense_variant	2/8	1	NM_022128.3	P1
RBKS	ENST00000449378.1	c.*1028G>A		3_prime_UTR_variant, NMD_transcript_variant	3/9	1
MRPL33	ENST00000448427.1	c.165-35973C>T		intron_variant, NMD_transcript_variant		4
RBKS	ENST00000453412.1	c.*124G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000168 AC: 42 AN: 250420 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000601

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000507 AC: 74 AN: 1460742 Hom.: 0 Cov.: 30 AF XY: 0.0000605 AC XY: 44 AN XY: 726762

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000517

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74238

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.101G>A (p.R34H) alteration is located in exon 2 (coding exon 2) of the RBKS gene. This alteration results from a G to A substitution at nucleotide position 101, causing the arginine (R) at amino acid position 34 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.88
MVP		0.86
MPC		0.088
ClinPred		0.18	T
GERP RS		5.8
Varity_R		0.81
gMVP		0.72

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: rs369972719; hg19: chr2-28081427; COSMIC: COSV104402933;