1-23691827-G-T

Position:

• chr1-23691827-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000975.5(RPL11):​c.4G>T​(p.Ala2Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPL11 NM_000975.5 missense, splice_region
• Scores: Splicing: ADA: 0.9763
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61

Genes affected

RPL11 (HGNC:10301): (ribosomal protein L11) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L5P family of ribosomal proteins. It is located in the cytoplasm. The protein probably associates with the 5S rRNA. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain 60S ribosomal protein L11 (size 176) in uniprot entity RL11_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000975.5
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL11	NM_000975.5	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	1/6	ENST00000643754.2	NP_000966.2
RPL11	NM_001199802.1	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	1/6		NP_001186731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL11	ENST00000643754.2	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	1/6		NM_000975.5	ENSP00000496250	A1
RPL11	ENST00000374550.8	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	1/6	1		ENSP00000363676	P4
RPL11	ENST00000443624.6	n.22G>T		splice_region_variant, non_coding_transcript_exon_variant	1/5	2
RPL11	ENST00000467075.2	c.4G>T	p.Ala2Ser	missense_variant, NMD_transcript_variant	1/6	3		ENSP00000493634

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RPL11-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 2 of the RPL11 protein (p.Ala2Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.57	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.27	T;.
Sift4G	Benign	0.43	T;.
Polyphen		0.0050	B;B
Vest4		0.39
MutPred		0.15		Gain of phosphorylation at A2 (P = 0.0287);Gain of phosphorylation at A2 (P = 0.0287);
MVP		0.97
MPC		0.66
ClinPred		0.84	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.020		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: rs1553121574; hg19: chr1-24018317;