17-8377635-C-T

Variant names:

• chr17-8377635-C-T
• rs1417316781
• NM_000987.5:c.367G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000987.5(RPL26):​c.367G>A​(p.Ala123Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPL26 NM_000987.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28045636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL26	NM_000987.5	c.367G>A	p.Ala123Thr	missense_variant	Exon 4 of 4	ENST00000648839.1	NP_000978.1
RPL26	NM_001315530.2	c.367G>A	p.Ala123Thr	missense_variant	Exon 4 of 4		NP_001302459.1
RPL26	NM_001315531.2	c.367G>A	p.Ala123Thr	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.367G>A	p.Ala123Thr	missense_variant	Exon 4 of 4		NM_000987.5	ENSP00000498177.1
ENSG00000263809	ENST00000582471.1	n.310-1531G>A		intron_variant	Intron 3 of 5	5		ENSP00000463847.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1 AN: 1458282 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725616

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 123 of the RPL26 protein (p.Ala123Thr). 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;T;T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	.;.;.;.;D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	2.9	M;M;M;M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.3	.;N;.;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.018	.;D;.;.;.
Sift4G	Benign	0.071	.;T;T;T;T
Polyphen		0.039	B;B;B;B;B
Vest4		0.48, 0.45, 0.49
MutPred		0.25		Gain of phosphorylation at A123 (P = 0.0058);Gain of phosphorylation at A123 (P = 0.0058);Gain of phosphorylation at A123 (P = 0.0058);Gain of phosphorylation at A123 (P = 0.0058);Gain of phosphorylation at A123 (P = 0.0058);
MVP		0.50
MPC		0.95
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.45

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: rs1417316781; hg19: chr17-8280953;