rs121434405

Positions:

• chr1-92833452-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000969.5(RPL5):​c.67C>T​(p.Arg23Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPL5 NM_000969.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.205

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-92833452-C-T is Pathogenic according to our data. Variant chr1-92833452-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92833452-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL5	NM_000969.5	c.67C>T	p.Arg23Ter	stop_gained	2/8	ENST00000370321.8	NP_000960.2
DIPK1A	NM_001252273.2	c.475-418G>A		intron_variant			NP_001239202.1
RPL5	NR_146333.1	n.196C>T		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL5	ENST00000370321.8	c.67C>T	p.Arg23Ter	stop_gained	2/8	1	NM_000969.5	ENSP00000359345	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2020	The p.R23* pathogenic mutation (also known as c.67C>T), located in coding exon 2 of the RPL5 gene, results from a C to T substitution at nucleotide position 67. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration was reported to occur de novo in an individual diagnosed with Diamond-Blackfan anemia (DBA) who was also born with cleft lip and palate (Gazda HT et al. Am. J. Hum. Genet., 2008 Dec;83:769-80), and has been detected in other DBA cohorts and in a congenital heart disease cohort (Smetanina NS et al. Pediatr Blood Cancer. 2015 Sep;62(9):1597-600; Jin SC et al. Nat. Genet. 2017 Nov;49(11):1593-1601). A study of induced pluripotent stem cells derived from a patient with this mutation reported defects in ribosome biogenesis and hematopoiesis (Garçon L et al. Blood. 2013 Aug;122(6):912-21). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 25, 2019	This sequence change creates a premature translational stop signal (p.Arg23*) in the RPL5 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Diamond-Blackfan anemia (PMID: 19061985) and an individual with congenital heart disease (PMID: 28991257). ClinVar contains an entry for this variant (Variation ID: 6179). Loss-of-function variants in RPL5 are known to be pathogenic (PMID: 19061985, 19773262). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23744582, 25525159, 28991257, 32368696, 33084842, 19061985) -

Diamond-Blackfan anemia 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.89
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121434405; hg19: chr1-93299009;