12-56044133-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001029.5(RPS26):c.327T>A(p.Arg109Arg) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.32

Publications

4 publications found

Variant links:

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]

RPS26 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia 10
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPS26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
RPS26	NM_001029.5 link	c.327T>A	p.Arg109Arg	synonymous_variant	Exon 4 of 4	ENST00000646449.2	NP_001020.2	P62854A0A024RB14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPS26	ENST00000646449.2 link	c.327T>A	p.Arg109Arg	synonymous_variant	Exon 4 of 4		NM_001029.5	ENSP00000496643.1	P62854
RPS26	ENST00000356464.10 link	c.327T>A	p.Arg109Arg	synonymous_variant	Exon 5 of 5	1		ENSP00000348849.5	P62854
RPS26	ENST00000552361.1 link	c.327T>A	p.Arg109Arg	synonymous_variant	Exon 5 of 5	5		ENSP00000450339.1	P62854
RPS26	ENST00000548590.1 link	n.1114T>A		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0757

AC:

11483

AN:

151750

Hom.:

1467

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0199

AC:

5013

AN:

251476

AF XY:

0.0144

show subpopulations

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 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.:

AF XY:

0.00668

AC XY:

4852

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.278

AC:

9254

AN:

33330

American (AMR)

AF:

0.0134

AC:

599

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00539

AC:

141

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000522

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000267

AC:

297

AN:

1111264

Other (OTH)

AF:

0.0169

AC:

1022

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

435

870

1305

1740

2175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0759

AC:

11525

AN:

151868

Hom.:

1477

Cov.:

AF XY:

0.0728

AC XY:

5407

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.265

AC:

10952

AN:

41298

American (AMR)

AF:

0.0260

AC:

396

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000624

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000780

AC:

AN:

67970

Other (OTH)

AF:

0.0417

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

420

840

1260

1680

2100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00854

Hom.:

Bravo

AF:

0.0864

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diamond-Blackfan anemia 10

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 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 specified

Benign:1

Mar 16, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Diamond-Blackfan anemia

Benign:1

May 10, 2016

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

5.7

(source)

DANN

Benign

0.78

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over