rs1060503545

Positions:

• chr1-92841839-G-A

Variant summary

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

The NM_000969.5(RPL5):​c.868G>A​(p.Ala290Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A290G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPL5 NM_000969.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

Genes affected

RPL5 (HGNC:10360): (ribosomal protein L5) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L18P family of ribosomal proteins and component of the 60S subunit. The encoded protein binds 5S rRNA to form a stable complex called the 5S ribonucleoprotein particle (RNP), which is necessary for the transport of nonribosome-associated cytoplasmic 5S rRNA to the nucleolus for assembly into ribosomes. The encoded protein may also function to inhibit tumorigenesis through the activation of downstream tumor suppressors and the downregulation of oncoprotein expression. Mutations in this gene have been identified in patients with Diamond-Blackfan Anemia (DBA). This gene is co-transcribed with the small nucleolar RNA gene U21, which is located in its fifth intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. [provided by RefSeq, Mar 2017]

DIPK1A (HGNC:32213): (divergent protein kinase domain 1A) This gene encodes a member of the FAM69 family of cysteine-rich type II transmembrane proteins. These proteins localize to the endoplasmic reticulum but their specific functions are unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

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/exons	MANE	UniProt
RPL5	NM_000969.5	c.868G>A	p.Ala290Thr	missense_variant	8/8	ENST00000370321.8
DIPK1A	NM_001252273.2	c.474+5344C>T		intron_variant
RPL5	NR_146333.1	n.927G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL5	ENST00000370321.8	c.868G>A	p.Ala290Thr	missense_variant	8/8	1	NM_000969.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 11, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RPL5-related disease. This sequence change replaces alanine with threonine at codon 290 of the RPL5 protein (p.Ala290Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.65	.;N;.
REVEL	Uncertain	0.37
Sift	Benign	0.097	.;T;.
Sift4G	Benign	0.17	.;T;.
Polyphen		0.54	P;P;.
Vest4		0.45
MutPred		0.26		Gain of phosphorylation at A290 (P = 0.0374);Gain of phosphorylation at A290 (P = 0.0374);.;
MVP		0.68
MPC		0.61
ClinPred		0.77	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.40

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: rs1060503545; hg19: chr1-93307396;