15-82538981-C-G

Position:

• chr15-82538981-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_001021.6(RPS17):​c.160G>C​(p.Val54Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: RPS17 NM_001021.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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]

ENSG00000260836 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• 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, 0.819
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS17	NM_001021.6	c.160G>C	p.Val54Leu	missense_variant	3/5	ENST00000647841.1	NP_001012.1
RPS17	NR_111943.2	n.482G>C		non_coding_transcript_exon_variant	2/4
RPS17	NR_111944.3	n.189G>C		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS17	ENST00000647841.1	c.160G>C	p.Val54Leu	missense_variant	3/5		NM_001021.6	ENSP00000498019.1
ENSG00000260836	ENST00000562833.2	c.1507G>C	p.Val503Leu	missense_variant	11/13	3		ENSP00000454786.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461632 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

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

Diamond-Blackfan anemia 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	.;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-2.3	.;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.034	.;D;D;.
Sift4G	Uncertain	0.050	.;T;D;.
Vest4		0.69, 0.72
MutPred		0.57		Loss of catalytic residue at V54 (P = 0.027);Loss of catalytic residue at V54 (P = 0.027);Loss of catalytic residue at V54 (P = 0.027);.;
MVP		0.46
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.65
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

LitVar

Other links and lift over

dbSNP: rs1222131687; hg19: chr15-83207732;