22-39312960-C-T

Position:

• chr22-39312960-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000216146.9(RPL3):​c.1192G>A​(p.Ala398Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000538 in 1,614,174 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (6 hom.)
• Consequence: RPL3 ENST00000216146.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007433325).
• BP6: Variant 22-39312960-C-T is Benign according to our data. Variant chr22-39312960-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2482982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL3	NM_000967.4	c.1192G>A	p.Ala398Thr	missense_variant	10/10	ENST00000216146.9	NP_000958.1
RPL3	NM_001033853.2	c.1045G>A	p.Ala349Thr	missense_variant	10/10		NP_001029025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL3	ENST00000216146.9	c.1192G>A	p.Ala398Thr	missense_variant	10/10	1	NM_000967.4	ENSP00000346001	P1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00141 AC: 354 AN: 251394 Hom.: 2 AF XY: 0.00142 AC XY: 193 AN XY: 135876

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0119

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000523 AC: 764 AN: 1461806 Hom.: 6 Cov.: 31 AF XY: 0.000545 AC XY: 396 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00793

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000872 AC XY: 65 AN XY: 74514

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000630 Hom.: 1

Bravo AF: 0.000672

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T
Eigen	Benign	0.070
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.16
Sift	Benign	0.16	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.0020	.;B
Vest4		0.59
MVP		0.44
MPC		0.66
ClinPred		0.023	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.56

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: rs141236265; hg19: chr22-39708965;