NM_000969.5:c.48C>A

Variant names:

• chr1-92833433-C-A
• rs148673599
• NM_000969.5:c.48C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000969.5(RPL5):​c.48C>A​(p.Tyr16*) 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, single submitter P:1
• Conservation: PhyloP100: 3.38

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 12 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 54 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-92833433-C-A is Pathogenic according to our data. Variant chr1-92833433-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1743930.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-92833433-C-A is described in Lovd as [Pathogenic]. Variant chr1-92833433-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL5	NM_000969.5	c.48C>A	p.Tyr16*	stop_gained	Exon 2 of 8	ENST00000370321.8	NP_000960.2
DIPK1A	NM_001252273.2	c.475-399G>T		intron_variant	Intron 4 of 4		NP_001239202.1
RPL5	NR_146333.1	n.177C>A		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL5	ENST00000370321.8	c.48C>A	p.Tyr16*	stop_gained	Exon 2 of 8	1	NM_000969.5	ENSP00000359345.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Pathogenic:1

Sep 04, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y16* pathogenic mutation (also known as c.48C>A), located in coding exon 2 of the RPL5 gene, results from a C to A substitution at nucleotide position 48. This changes the amino acid from a tyrosine to a stop codon within coding exon 2. This nonsense mutation was reportedly de novo in a male DBA patient with cleft palate, abnormal right thumb malformations, growth retardation, and steroid response (Boria I et al. Hum Mutat. 2010;31(12):1269-1279). A mutation (c.48C>G) resulting in the same amino acid change, was reported in a female DBA patient diagnosed at birth and who was responsive to high steroid doses and also received red blood cell transfusions. In the same study, another mutation (c.46_47insA) resulting in the same amino acid change was reported in a male DBA patient diagnosed at birth with micrognathia, hypertelorism, soft cleft palate, triphalangeal right thumb, widened webbed space between first and second toes, and hypospadias (Gazda HT et al. Am J Hum Genet. 2008;83(6):769-780). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.81
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs148673599; hg19: chr1-93298990; COSMIC: COSV59873416; COSMIC: COSV59873416;