3-139005706-C-A

Variant names:

• chr3-139005706-C-A
• rs536328953
• NM_001134659.1:c.563G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001134659.1(PRR23A):​c.563G>T​(p.Ser188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,613,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: PRR23A NM_001134659.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.151

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031767637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR23A	NM_001134659.1	c.563G>T	p.Ser188Ile	missense_variant	Exon 1 of 1	ENST00000383163.4	NP_001128131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR23A	ENST00000383163.4	c.563G>T	p.Ser188Ile	missense_variant	Exon 1 of 1	6	NM_001134659.1	ENSP00000372649.2
MRPS22	ENST00000495075.5	c.-532C>A		upstream_gene_variant		1		ENSP00000418008.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000185 AC: 46 AN: 248820 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135148

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 271 AN: 1461604 Hom.: 1 Cov.: 56 AF XY: 0.000205 AC XY: 149 AN XY: 727066

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74396

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.563G>T (p.S188I) alteration is located in exon 1 (coding exon 1) of the PRR23A gene. This alteration results from a G to T substitution at nucleotide position 563, causing the serine (S) at amino acid position 188 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.3
DANN	Benign	0.48
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Benign	0.21	T
Polyphen		0.057	B
Vest4		0.19
MVP		0.040
MPC		0.75
ClinPred		0.0071	T
GERP RS		0.59
Varity_R		0.085
gMVP		0.18

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: rs536328953; hg19: chr3-138724548; COSMIC: COSV67214397; COSMIC: COSV67214397;