17-8377659-G-A

Variant names:

• chr17-8377659-G-A
• rs1907208899
• NM_000987.5:c.343C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_000987.5(RPL26):​c.343C>T​(p.Arg115Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RPL26 NM_000987.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL26	NM_000987.5	c.343C>T	p.Arg115Cys	missense_variant	Exon 4 of 4	ENST00000648839.1	NP_000978.1
RPL26	NM_001315530.2	c.343C>T	p.Arg115Cys	missense_variant	Exon 4 of 4		NP_001302459.1
RPL26	NM_001315531.2	c.343C>T	p.Arg115Cys	missense_variant	Exon 4 of 4		NP_001302460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL26	ENST00000648839.1	c.343C>T	p.Arg115Cys	missense_variant	Exon 4 of 4		NM_000987.5	ENSP00000498177.1
ENSG00000263809	ENST00000582471.1	n.310-1555C>T		intron_variant	Intron 3 of 5	5		ENSP00000463847.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459322 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the RPL26 protein (p.Arg115Cys). 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. 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Uncertain	0.68	D;D;D;D;D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	.;.;.;.;D
M_CAP	Benign	0.0058	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	2.9	M;M;M;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.7	.;D;.;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.012	.;D;.;.;.
Sift4G	Uncertain	0.021	.;D;D;D;D
Polyphen		0.014	B;B;B;B;B
Vest4		0.79, 0.79, 0.78, 0.80
MutPred		0.71		Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);
MVP		0.56
MPC		2.5
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.66
gMVP		0.87

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: rs1907208899; hg19: chr17-8280977; COSMIC: COSV105875834; COSMIC: COSV105875834;