chr9-19376395-A-G

Variant names:

• chr9-19376395-A-G
• rs146329014
• NM_001010.3:c.655-7T>C

Variant summary

Our verdict is Benign. The variant received -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, 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, 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1599 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6	NM_001010.3	c.655-7T>C		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000380394.9	NP_001001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6	ENST00000380394.9	c.655-7T>C		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_001010.3	ENSP00000369757.4
RPS6	ENST00000380384.5	c.562-7T>C		splice_region_variant, intron_variant	Intron 4 of 4	1		ENSP00000369745.1
RPS6	ENST00000315377.4	c.562-7T>C		splice_region_variant, intron_variant	Intron 5 of 5	3		ENSP00000369743.1
RPS6	ENST00000498815.1	n.347-7T>C		splice_region_variant, intron_variant	Intron 1 of 1	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

GnomAD2 exomes AF: 0.00280 AC: 701 AN: 250054 AF XY: 0.00211

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 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 AC: 1117 AN: 33430

Gnomad4 AMR exome AF: 0.00222 AC: 99 AN: 44608

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26114

Gnomad4 EAS exome AF: 0.000454 AC: 18 AN: 39676

Gnomad4 SAS exome AF: 0.000162 AC: 14 AN: 86166

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53414

Gnomad4 NFE exome AF: 0.0000144 AC: 16 AN: 1111670

Gnomad4 Remaining exome AF: 0.00275 AC: 166 AN: 60380

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 AC: 0.0364363 AN: 0.0364363

Gnomad4 AMR AF: 0.00327 AC: 0.00326712 AN: 0.00326712

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00174 AC: 0.00174014 AN: 0.00174014

Gnomad4 SAS AF: 0.000207 AC: 0.000206954 AN: 0.000206954

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000103 AC: 0.000102902 AN: 0.000102902

Gnomad4 OTH AF: 0.00851 AC: 0.00851466 AN: 0.00851466

Alfa AF: 0.00551 Hom.: 8

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

Apr 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
Mutation Taster		=100/0	polymorphism

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;