9-19376395-A-G

Position:

• chr9-19376395-A-G

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.655-7T>C 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 0.00188 in 1,613,514 control chromosomes in the GnomAD database, including 54 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 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (26 hom.)
• Consequence: RPS6 NM_001010.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001752
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.02

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=-0.72).
• BP6: Variant 9-19376395-A-G is Benign according to our data. Variant chr9-19376395-A-G is described in ClinVar as [Benign]. Clinvar id is 714421.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1599/152288) while in subpopulation AFR AF= 0.0364 (1514/41552). AF 95% confidence interval is 0.0349. There are 28 homozygotes in gnomad4. There are 749 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1599 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6	NM_001010.3	c.655-7T>C		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.655-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001010.3	P1
RPS6	ENST00000380384.5	c.562-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
RPS6	ENST00000315377.4	c.562-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3
RPS6	ENST00000498815.1	n.347-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1589 AN: 152170 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00280 AC: 701 AN: 250054 Hom.: 9 AF XY: 0.00211 AC XY: 285 AN XY: 135164

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00115

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000982 AC: 1435 AN: 1461226 Hom.: 26 Cov.: 31 AF XY: 0.000874 AC XY: 635 AN XY: 726904

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000454

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.0105 AC: 1599 AN: 152288 Hom.: 28 Cov.: 32 AF XY: 0.0101 AC XY: 749 AN XY: 74464

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00592 Hom.: 6

Bravo AF: 0.0121

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

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

Apr 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.040		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: rs146329014; hg19: chr9-19376393;