chr1-23691827-G-T

Variant names:

• chr1-23691827-G-T
• rs1553121574
• NM_000975.5:c.4G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified 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
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000975.5. 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
	RPL11	NM_000975.5	MANE Select	c.4G>T	p.Ala2Ser	missense splice_region	Exon 1 of 6	NP_000966.2
	RPL11	NM_001199802.1		c.4G>T	p.Ala2Ser	missense splice_region	Exon 1 of 6	NP_001186731.1	P62913-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL11	ENST00000643754.2	MANE Select	c.4G>T	p.Ala2Ser	missense splice_region	Exon 1 of 6	ENSP00000496250.1	P62913-1
	RPL11	ENST00000374550.8	TSL:1	c.4G>T	p.Ala2Ser	missense splice_region	Exon 1 of 6	ENSP00000363676.4	P62913-2
	RPL11	ENST00000933799.1		c.4G>T	p.Ala2Ser	missense splice_region	Exon 1 of 7	ENSP00000603858.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
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
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.6
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
Vest4		0.39
MutPred		0.15		Gain of phosphorylation at A2 (P = 0.0287)
MVP		0.97
MPC		0.66
ClinPred		0.84	D
GERP RS		5.3
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.53
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs1553121574; hg19: chr1-24018317;