chr3-139006180-C-T

Position:

• chr3-139006180-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134659.1(PRR23A):​c.89G>A​(p.Arg30Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRR23A NM_001134659.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716

Genes affected

PRR23A (HGNC:37172): (proline rich 23A)

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29021046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRR23A	NM_001134659.1	c.89G>A	p.Arg30Gln	missense_variant	1/1	ENST00000383163.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRR23A	ENST00000383163.4	c.89G>A	p.Arg30Gln	missense_variant	1/1		NM_001134659.1	P1
MRPS22	ENST00000495075.5	c.-143+85C>T		intron_variant		1		P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.16e-7 AC: 1 AN: 1395838 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 688846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000282

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.: 31

ExAC AF: 0.00000972 AC: 1

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

Mar 07, 2024

The c.89G>A (p.R30Q) alteration is located in exon 1 (coding exon 1) of the PRR23A gene. This alteration results from a G to A substitution at nucleotide position 89, causing the arginine (R) at amino acid position 30 to be replaced by a glutamine (Q). 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	0.22
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.023	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.096
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.20
MutPred		0.61		Gain of methylation at K27 (P = 0.046);
MVP		0.092
MPC		1.7
ClinPred		0.95	D
GERP RS		1.6
Varity_R		0.33
gMVP		0.21

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: rs745392892; hg19: chr3-138725022; COSMIC: COSV104701556;