15-82540122-C-A

Position:

• chr15-82540122-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001021.6(RPS17):​c.14G>T​(p.Arg5Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RPS17 NM_001021.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

Genes affected

RPS17 (HGNC:10397): (ribosomal protein S17) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S17E family of ribosomal proteins and is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia 4. Alternative splicing of this gene results in multiple transcript variants. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPS17. . Trascript score misZ 3.1895 (greater than threshold 3.09). GenCC has associacion of gene with Diamond-Blackfan anemia 4, Diamond-Blackfan anemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS17	NM_001021.6	c.14G>T	p.Arg5Leu	missense_variant	2/5	ENST00000647841.1
RPS17	NR_111943.2	n.336G>T		non_coding_transcript_exon_variant	1/4
RPS17	NR_111944.3	n.43G>T		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS17	ENST00000647841.1	c.14G>T	p.Arg5Leu	missense_variant	2/5		NM_001021.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	.;T;T;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.023	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.5	.;D;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	.;D;D;.
Sift4G	Uncertain	0.015	.;D;D;.
Vest4		0.76, 0.73
MutPred		0.68		Loss of methylation at R3 (P = 0.0336);Loss of methylation at R3 (P = 0.0336);Loss of methylation at R3 (P = 0.0336);.;
MVP		0.59
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-83208873;