3-139019886-C-G

Position:

• chr3-139019886-C-G

Variant summary

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

The NM_001013650.2(PRR23B):​c.776G>C​(p.Arg259Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRR23B NM_001013650.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.362

Genes affected

PRR23B (HGNC:33764): (proline rich 23B)

MRPS22 (HGNC:14508): (mitochondrial ribosomal protein S22) 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 28S subunit protein that does not seem to have a counterpart in prokaryotic and fungal-mitochondrial ribosomes. This gene lies telomeric of and is transcribed in the opposite direction from the forkhead box L2 gene. A pseudogene corresponding to this gene is found on chromosome Xq. [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
PRR23B	NM_001013650.2	c.776G>C	p.Arg259Pro	missense_variant	1/1	ENST00000329447.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRR23B	ENST00000329447.5	c.776G>C	p.Arg259Pro	missense_variant	1/1		NM_001013650.2	P1
MRPS22	ENST00000495075.5	c.-143+13791C>G		intron_variant		1		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452330 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000463

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 27, 2024

The c.776G>C (p.R259P) alteration is located in exon 1 (coding exon 1) of the PRR23B gene. This alteration results from a G to C substitution at nucleotide position 776, causing the arginine (R) at amino acid position 259 to be replaced by a proline (P). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0032	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.62		Gain of loop (P = 3e-04);
MVP		0.072
MPC		1.7
ClinPred		0.98	D
GERP RS		1.8
Varity_R		0.80
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1576489828; hg19: chr3-138738728;