22-39315440-G-A

Variant names:

• chr22-39315440-G-A
• NM_000967.4:c.617C>T

Variant summary

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

The NM_000967.4(RPL3):​c.617C>T​(p.Pro206Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,634 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: RPL3 NM_000967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

Genes affected

RPL3 (HGNC:10332): (ribosomal protein L3) Ribosomes, the complexes that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L3P family of ribosomal proteins and it is located in the cytoplasm. The protein can bind to the HIV-1 TAR mRNA, and it has been suggested that the protein contributes to tat-mediated transactivation. This gene is co-transcribed with several small nucleolar RNA genes, which are located in several of this gene's introns. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

SNORD83A (HGNC:17131): (small nucleolar RNA, C/D box 83A) Intronic regions of ribosomal protein genes can harbor noncoding small nucleolar RNAs (snoRNAs), like SNORD83A, which are generated during pre-mRNA processing. snoRNAs form part of the small nucleolar ribonucleoprotein particles (snoRNPs) involved in pre-rRNA processing and modification. snoRNAs of the box C/D class, like SNORD83A, function in 2-prime-O-ribose methylation of rRNAs (Duga et al., 2000 [PubMed 10684968]).[supplied by OMIM, Mar 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 rank	MANE	Protein	UniProt
RPL3	NM_000967.4	c.617C>T	p.Pro206Leu	missense_variant	Exon 5 of 10	ENST00000216146.9	NP_000958.1
RPL3	NM_001033853.2	c.470C>T	p.Pro157Leu	missense_variant	Exon 5 of 10		NP_001029025.1
SNORD83A	NR_000027.1	n.-133C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL3	ENST00000216146.9	c.617C>T	p.Pro206Leu	missense_variant	Exon 5 of 10	1	NM_000967.4	ENSP00000346001.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461634 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.617C>T (p.P206L) alteration is located in exon 5 (coding exon 5) of the RPL3 gene. This alteration results from a C to T substitution at nucleotide position 617, causing the proline (P) at amino acid position 206 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	.;M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.020	D;D;.;.
Polyphen		0.0040	B;B;.;.
Vest4		0.35
MutPred		0.44		.;Gain of sheet (P = 0.1539);.;.;
MVP		0.36
MPC		0.71
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.38
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39711445;