1-23694734-C-T

Variant names:

• chr1-23694734-C-T
• rs8880
• NM_000975.5:c.339C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000975.5(RPL11):​c.339C>T​(p.Ile113Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,614,106 control chromosomes in the GnomAD database, including 1,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (69 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1225 hom.)
• Consequence: RPL11 NM_000975.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0180
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-23694734-C-T is Benign according to our data. Variant chr1-23694734-C-T is described in ClinVar as Benign. ClinVar VariationId is 296821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.018 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3793/152276) while in subpopulation NFE AF = 0.0393 (2671/68014). AF 95% confidence interval is 0.038. There are 69 homozygotes in GnomAd4. There are 1751 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3793 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL11	NM_000975.5	MANE Select	c.339C>T	p.Ile113Ile	synonymous	Exon 4 of 6	NP_000966.2
	RPL11	NM_001199802.1		c.336C>T	p.Ile112Ile	synonymous	Exon 4 of 6	NP_001186731.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL11	ENST00000643754.2	MANE Select	c.339C>T	p.Ile113Ile	synonymous	Exon 4 of 6	ENSP00000496250.1
	RPL11	ENST00000374550.8	TSL:1	c.336C>T	p.Ile112Ile	synonymous	Exon 4 of 6	ENSP00000363676.4
	RPL11	ENST00000458455.2	TSL:1	c.306C>T	p.Ile102Ile	synonymous	Exon 3 of 5	ENSP00000398888.2

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3795 AN: 152158 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0246 AC: 6180 AN: 251458 AF XY: 0.0242

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0368 AC: 53781 AN: 1461830 Hom.: 1225 Cov.: 31 AF XY: 0.0356 AC XY: 25895 AN XY: 727212

African (AFR) AF: 0.00565 AC: 189 AN: 33480

American (AMR) AF: 0.0135 AC: 606 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 287 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00796 AC: 687 AN: 86256

European-Finnish (FIN) AF: 0.0330 AC: 1765 AN: 53420

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.0433 AC: 48192 AN: 1111956

Other (OTH) AF: 0.0330 AC: 1990 AN: 60392

GnomAD4 genome AF: 0.0249 AC: 3793 AN: 152276 Hom.: 69 Cov.: 32 AF XY: 0.0235 AC XY: 1751 AN XY: 74462

African (AFR) AF: 0.00775 AC: 322 AN: 41560

American (AMR) AF: 0.0173 AC: 265 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.0335 AC: 356 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0393 AC: 2671 AN: 68014

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0329 Hom.: 186

Bravo AF: 0.0226

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 7 Benign:2

Aug 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Diamond-Blackfan anemia Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 25, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.56
PhyloP100		0.018
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs8880; hg19: chr1-24021224;