rs1553285028

Variant names:

• chr1-92833641-A-G
• rs1553285028
• NM_000969.5:c.170A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000969.5(RPL5):​c.170A>G​(p.Asn57Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RPL5 NM_000969.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.24
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL5	NM_000969.5	c.170A>G	p.Asn57Ser	missense_variant	Exon 3 of 8	ENST00000370321.8	NP_000960.2
RPL5	NR_146333.1	n.299A>G		non_coding_transcript_exon_variant	Exon 3 of 8
DIPK1A	NM_001252273.2	c.475-607T>C		intron_variant	Intron 4 of 4		NP_001239202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL5	ENST00000370321.8	c.170A>G	p.Asn57Ser	missense_variant	Exon 3 of 8	1	NM_000969.5	ENSP00000359345.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Dec 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with RPL5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 57 of the RPL5 protein (p.Asn57Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. -

Diamond-Blackfan anemia 6 Uncertain:1

Feb 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	.;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Pathogenic	3.2	M;.;M;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.0	.;.;D;.;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0080	.;.;D;.;D
Sift4G	Uncertain	0.036	.;.;D;.;T
Polyphen		0.027	B;.;B;.;.
Vest4		0.82
MutPred		0.72		Gain of phosphorylation at N57 (P = 0.0951);.;Gain of phosphorylation at N57 (P = 0.0951);Gain of phosphorylation at N57 (P = 0.0951);.;
MVP		0.85
MPC		0.42
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.80
Mutation Taster		=20/80	disease causing

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: rs1553285028; hg19: chr1-93299198;