1-92832117-G-A

Position:

• chr1-92832117-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000969.5(RPL5):​c.3G>A​(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPL5 NM_000969.5 start_lost, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-92832117-G-A is Pathogenic according to our data. Variant chr1-92832117-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1736900.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-92832117-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPL5	NM_000969.5	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/8	ENST00000370321.8
RPL5	NR_146333.1	n.132G>A		splice_region_variant, non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL5	ENST00000370321.8	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/8	1	NM_000969.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2015

The p.M1? pathogenic mutation (also known as c.3G>A), located in coding exon 1 of the RPL5 gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. In addition, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This mutation has been described in a Japanese individual with a clinical diagnosis of Diamond-Blackfan anemia (DBA), who had thumb polydactyly in addition to red blood cell aplasia (Konno Y et al. Haematologica 2010 Aug; 95(8):1293-9). Multiple other nucleotide substitutions that alter the initiation codon have also been reported in individuals with DBA (Konno Y et al. Haematologica 2010 Aug; 95(8):1293-9; Boria I et al. Hum. Mutat. 2010 Dec; 31(12):1269-79; Quarello P et al. Haematologica 2010 Feb; 95(2):206-13). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, 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	0.35
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.6	.;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	.;D;.
Sift4G	Uncertain	0.024	.;D;.
Polyphen		0.13	B;B;.
Vest4		0.94
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0155);Gain of catalytic residue at M1 (P = 0.0155);Gain of catalytic residue at M1 (P = 0.0155);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.61
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.060		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: rs138710531; hg19: chr1-93297674;