17-8377625-C-T

Position:

• chr17-8377625-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000987.5(RPL26):​c.377G>A​(p.Arg126His) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,456,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RPL26 NM_000987.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.06

Genes affected

RPL26 (HGNC:10327): (ribosomal protein L26) 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 L24P family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Mutations in this gene result in Diamond-Blackfan anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ENSG00000263809 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33487153).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL26	NM_000987.5	c.377G>A	p.Arg126His	missense_variant	4/4	ENST00000648839.1	NP_000978.1
RPL26	NM_001315530.2	c.377G>A	p.Arg126His	missense_variant	4/4		NP_001302459.1
RPL26	NM_001315531.2	c.377G>A	p.Arg126His	missense_variant	4/4		NP_001302460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL26	ENST00000648839.1	c.377G>A	p.Arg126His	missense_variant	4/4		NM_000987.5	ENSP00000498177.1
ENSG00000263809	ENST00000582471.1	n.310-1521G>A		intron_variant		5		ENSP00000463847.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456810 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 126 of the RPL26 protein (p.Arg126His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RPL26-related conditions. ClinVar contains an entry for this variant (Variation ID: 945300). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2016	The p.R126H variant (also known as c.377G>A), located in coding exon 3 of the RPL26 gene, results from a G to A substitution at nucleotide position 377. The arginine at codon 126 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 05, 2019

- -

Diamond-Blackfan anemia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;.;.;.;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L;L;L;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	.;D;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.061	.;T;.;.;.
Sift4G	Benign	0.094	.;T;T;T;T
Polyphen		0.0020	B;B;B;B;B
Vest4		0.50, 0.50, 0.46, 0.50
MutPred		0.30		Loss of methylation at K122 (P = 0.0652);Loss of methylation at K122 (P = 0.0652);Loss of methylation at K122 (P = 0.0652);Loss of methylation at K122 (P = 0.0652);Loss of methylation at K122 (P = 0.0652);
MVP		0.62
MPC		1.2
ClinPred		0.96	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.56

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: rs932068728; hg19: chr17-8280943; COSMIC: COSV99549537; COSMIC: COSV99549537;