17-8377641-G-A

Position:

• chr17-8377641-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000987.5(RPL26):​c.361C>T​(p.Arg121Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,458,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RPL26 NM_000987.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL26	NM_000987.5	c.361C>T	p.Arg121Trp	missense_variant	4/4	ENST00000648839.1	NP_000978.1
RPL26	NM_001315530.2	c.361C>T	p.Arg121Trp	missense_variant	4/4		NP_001302459.1
RPL26	NM_001315531.2	c.361C>T	p.Arg121Trp	missense_variant	4/4		NP_001302460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL26	ENST00000648839.1	c.361C>T	p.Arg121Trp	missense_variant	4/4		NM_000987.5	ENSP00000498177	P1
	ENST00000666354.1	n.154-3404G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248430 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458228 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725620

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with RPL26-related conditions. This variant is present in population databases (rs763691423, ExAC 0.006%). This sequence change replaces arginine with tryptophan at codon 121 of the RPL26 protein (p.Arg121Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Benign	0.92
DEOGEN2	Uncertain	0.59	D;D;D;D;D
Eigen	Benign	0.073
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;.;.;.;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.1	.;D;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.037	.;D;.;.;.
Sift4G	Uncertain	0.010	.;D;D;D;D
Polyphen		0.072	B;B;B;B;B
Vest4		0.59, 0.60, 0.56
MutPred		0.61		Gain of catalytic residue at L119 (P = 0.0081);Gain of catalytic residue at L119 (P = 0.0081);Gain of catalytic residue at L119 (P = 0.0081);Gain of catalytic residue at L119 (P = 0.0081);Gain of catalytic residue at L119 (P = 0.0081);
MVP		0.47
MPC		1.0
ClinPred		0.85	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.72

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: rs763691423; hg19: chr17-8280959;