1-92832117-G-A

Variant names:

• chr1-92832117-G-A
• rs138710531
• NM_000969.5:c.3G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• 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]

RPL5 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 1736900.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000969.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL5	NM_000969.5	MANE Select	c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 8	NP_000960.2
	RPL5	NR_146333.1		n.132G>A		splice_region non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL5	ENST00000370321.8	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 8	ENSP00000359345.2	P46777
	RPL5	ENST00000880515.1		c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 8	ENSP00000550574.1
	RPL5	ENST00000880516.1		c.3G>A	p.Met1?	start_lost splice_region	Exon 1 of 8	ENSP00000550575.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Diamond-Blackfan anemia (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.13	T
PhyloP100		5.6
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.024	D
Polyphen		0.13	B
Vest4		0.94
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0155)
MVP		0.98
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.51	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.61
gMVP		0.73
Mutation Taster		=1/199	disease causing

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

Other links and lift over

dbSNP: rs138710531; hg19: chr1-93297674;