15-82538982-A-G

Position:

• chr15-82538982-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001021.6(RPS17):​c.159T>C​(p.Tyr53=) variant causes a synonymous change. The variant allele was found at a frequency of 0.306 in 1,613,126 control chromosomes in the GnomAD database, including 78,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.26 (5746 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72396 hom.)
• Consequence: RPS17 NM_001021.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.74

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-82538982-A-G is Benign according to our data. Variant chr15-82538982-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS17	NM_001021.6	c.159T>C	p.Tyr53=	synonymous_variant	3/5	ENST00000647841.1
RPS17	NR_111943.2	n.481T>C		non_coding_transcript_exon_variant	2/4
RPS17	NR_111944.3	n.188T>C		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS17	ENST00000647841.1	c.159T>C	p.Tyr53=	synonymous_variant	3/5		NM_001021.6	P1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40180 AN: 151992 Hom.: 5747 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.277

GnomAD4 exome AF: 0.310 AC: 452667 AN: 1461016 Hom.: 72396 Cov.: 34 AF XY: 0.315 AC XY: 228914 AN XY: 726838

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.312

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.421

Gnomad4 FIN exome AF: 0.377

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.264 AC: 40172 AN: 152110 Hom.: 5746 Cov.: 32 AF XY: 0.267 AC XY: 19847 AN XY: 74364

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.277

Alfa AF: 0.264 Hom.: 525

Bravo AF: 0.243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2017

The c.159 T>C (Y53Y) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. No population data for this variant is available due to low coverage of the RPS17 gene (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant occurs at a position that is conserved across species. However, the variant is a synonymous change which does not affect the amino acid sequence, and in silico analysis predicts this variant likely does not affect splicing. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Diamond-Blackfan anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.3
DANN	Benign	0.68
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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: rs6991; hg19: chr15-83207733;