9-19378522-G-C

Position:

• chr9-19378522-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001010.3(RPS6):​c.350-8C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,610,138 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00092 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: RPS6 NM_001010.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003043
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.393

Genes affected

RPS6 (HGNC:10429): (ribosomal protein S6) 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 cytoplasmic ribosomal protein that is a component of the 40S subunit. The protein belongs to the S6E family of ribosomal proteins. It is the major substrate of protein kinases in the ribosome, with subsets of five C-terminal serine residues phosphorylated by different protein kinases. Phosphorylation is induced by a wide range of stimuli, including growth factors, tumor-promoting agents, and mitogens. Dephosphorylation occurs at growth arrest. The protein may contribute to the control of cell growth and proliferation through the selective translation of particular classes of mRNA. 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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-19378522-G-C is Benign according to our data. Variant chr9-19378522-G-C is described in ClinVar as [Benign]. Clinvar id is 708362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000919 (140/152258) while in subpopulation EAS AF= 0.0204 (106/5188). AF 95% confidence interval is 0.0173. There are 2 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6	NM_001010.3	c.350-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000380394.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6	ENST00000380394.9	c.350-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001010.3	P1
RPS6	ENST00000380384.5	c.257-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
RPS6	ENST00000315377.4	c.257-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152140 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00212 AC: 521 AN: 245520 Hom.: 8 AF XY: 0.00202 AC XY: 268 AN XY: 132758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.000720

Gnomad FIN exome AF: 0.000882

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000794 AC: 1158 AN: 1457880 Hom.: 15 Cov.: 31 AF XY: 0.000794 AC XY: 576 AN XY: 725130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.0203

Gnomad4 SAS exome AF: 0.000797

Gnomad4 FIN exome AF: 0.000862

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.000781

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152258 Hom.: 2 Cov.: 33 AF XY: 0.00114 AC XY: 85 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0204

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.096
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: rs117840373; hg19: chr9-19378520;