8-144791286-C-A

Position:

• chr8-144791286-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001317782.2(RPL8):​c.490G>T​(p.Ala164Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,138 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPL8 NM_001317782.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63

Genes affected

RPL8 (HGNC:10368): (ribosomal protein L8) 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 L2P family of ribosomal proteins. It is located in the cytoplasm. In rat, the protein associates with the 5.8S rRNA, very likely participates in the binding of aminoacyl-tRNA, and is a constituent of the elongation factor 2-binding site at the ribosomal subunit interface. Alternatively spliced transcript variants encoding the same protein exist. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL8	NM_001317782.2	c.490G>T	p.Ala164Ser	missense_variant	3/5	ENST00000528957.6	NP_001304711.1
RPL8	NM_000973.5	c.490G>T	p.Ala164Ser	missense_variant	4/6		NP_000964.1
RPL8	NM_001317771.2	c.490G>T	p.Ala164Ser	missense_variant	4/6		NP_001304700.1
RPL8	NM_033301.3	c.490G>T	p.Ala164Ser	missense_variant	4/6		NP_150644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL8	ENST00000528957.6	c.490G>T	p.Ala164Ser	missense_variant	3/5	1	NM_001317782.2	ENSP00000433464	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725900

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.490G>T (p.A164S) alteration is located in exon 4 (coding exon 3) of the RPL8 gene. This alteration results from a G to T substitution at nucleotide position 490, causing the alanine (A) at amino acid position 164 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;T;.;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	.;D;.;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	5.0	H;.;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;.;D
Polyphen		0.69	P;.;P;P;.;.
Vest4		0.90
MutPred		0.91		Gain of disorder (P = 0.0305);.;Gain of disorder (P = 0.0305);Gain of disorder (P = 0.0305);.;Gain of disorder (P = 0.0305);
MVP		0.78
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1826503531; hg19: chr8-146016671;