NM_000967.4:c.664G>A

Variant names:

• chr22-39315393-C-T
• rs943345187
• NM_000967.4:c.664G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000967.4(RPL3):​c.664G>A​(p.Val222Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPL3 NM_000967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000967.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL3	NM_000967.4	MANE Select	c.664G>A	p.Val222Met	missense	Exon 5 of 10	NP_000958.1	P39023
	RPL3	NM_001033853.2		c.517G>A	p.Val173Met	missense	Exon 5 of 10	NP_001029025.1
	SNORD83A	NR_000027.1		n.-86G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL3	ENST00000216146.9	TSL:1 MANE Select	c.664G>A	p.Val222Met	missense	Exon 5 of 10	ENSP00000346001.3	P39023
	RPL3	ENST00000401609.5	TSL:1	c.508G>A	p.Val170Met	missense	Exon 4 of 9	ENSP00000386101.1	G5E9G0
	RPL3	ENST00000465618.5	TSL:1	n.1504G>A		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727116

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Polyphen		0.17	B
Vest4		0.84
MutPred		0.85		Loss of catalytic residue at V222 (P = 0.0355)
MVP		0.59
MPC		1.0
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.82
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs943345187; hg19: chr22-39711398;