rs56696262

chr12-56044133-T-Achr12-56044133-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001029.5(RPS26):c.327T>A(p.Arg109=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,612,816 control chromosomes in the GnomAD database, including 2,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R109R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.076 (1477 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (1345 hom.)
• Consequence: RPS26 NM_001029.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.32

Genes affected

RPS26 (HGNC:10414): (ribosomal protein S26) This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S26E family of ribosomal proteins. Mutations in this gene are found in Diamond-Blackfan anemia 10. There are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-56044133-T-A is Benign according to our data. Variant chr12-56044133-T-A is described in ClinVar as [Benign]. Clinvar id is 309860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS26	NM_001029.5	c.327T>A	p.Arg109=	synonymous_variant	4/4	ENST00000646449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS26	ENST00000646449.2	c.327T>A	p.Arg109=	synonymous_variant	4/4		NM_001029.5	P1
RPS26	ENST00000356464.10	c.327T>A	p.Arg109=	synonymous_variant	5/5	1		P1
RPS26	ENST00000552361.1	c.327T>A	p.Arg109=	synonymous_variant	5/5	5		P1
RPS26	ENST00000548590.1	n.1114T>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11483 AN: 151750 Hom.: 1467 Cov.: 31

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.0422

GnomAD3 exomes AF: 0.0199 AC: 5013 AN: 251476 Hom.: 598 AF XY: 0.0144 AC XY: 1959 AN XY: 135910

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00781 AC: 11409 AN: 1460948 Hom.: 1345 Cov.: 30 AF XY: 0.00668 AC XY: 4852 AN XY: 726888

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000267

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0759 AC: 11525 AN: 151868 Hom.: 1477 Cov.: 31 AF XY: 0.0728 AC XY: 5407 AN XY: 74236

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.00854 Hom.: 34

Bravo AF: 0.0864

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diamond-Blackfan anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2016

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	5.7
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs56696262; hg19: chr12-56437917;