1-23693872-C-T

Variant names:

• chr1-23693872-C-T
• rs121434389
• NM_000975.5:c.223C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000975.5(RPL11):​c.223C>T​(p.Arg75*) variant causes a stop gained change. 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPL11 NM_000975.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.01
• Publications: 5 publications found

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]

RPL11 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-23693872-C-T is Pathogenic according to our data. Variant chr1-23693872-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL11	NM_000975.5	c.223C>T	p.Arg75*	stop_gained	Exon 3 of 6	ENST00000643754.2	NP_000966.2
RPL11	NM_001199802.1	c.220C>T	p.Arg74*	stop_gained	Exon 3 of 6		NP_001186731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL11	ENST00000643754.2	c.223C>T	p.Arg75*	stop_gained	Exon 3 of 6		NM_000975.5	ENSP00000496250.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000736 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 7 Pathogenic:4

Apr 15, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000005751 / PMID: 19061985). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Dec 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jun 26, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4_MOD,PM2

not provided Pathogenic:1

Nov 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 19061985)

Diamond-Blackfan anemia Pathogenic:1

Feb 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RPL11 are known to be pathogenic (PMID: 19773262, 19061985). This variant has been reported to be de novo in an individual affected with Diamond-Blackfan anemia (PMID: 19061985). ClinVar contains an entry for this variant (Variation ID: 5751). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg75*) in the RPL11 gene. It is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	39
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.46
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		6.0
PROVEAN	Benign	0.0	.;.;.
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
Vest4		0.0
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121434389; hg19: chr1-24020362; COSMIC: COSV65778686;