6-7404480-A-C

Position:

• chr6-7404480-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000379834.7(RIOK1):​c.917A>C​(p.Gln306Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIOK1 ENST00000379834.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.02

Genes affected

RIOK1 (HGNC:18656): (RIO kinase 1) The protein encoded by this gene competes with pICln for inclusion in the protein arginine methyltransferase 5 complex. This complex targets substrates for dimethylation. The encoded protein is essential for the last steps in the maturation of 40S subunits. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIOK1	NM_031480.3	c.917A>C	p.Gln306Pro	missense_variant	10/17	ENST00000379834.7	NP_113668.2
RIOK1	NM_001348194.2	c.605A>C	p.Gln202Pro	missense_variant	10/17		NP_001335123.1
RIOK1	XM_011514933.4	c.953A>C	p.Gln318Pro	missense_variant	10/17		XP_011513235.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIOK1	ENST00000379834.7	c.917A>C	p.Gln306Pro	missense_variant	10/17	1	NM_031480.3	ENSP00000369162	P1
RIOK1	ENST00000264874.7	n.602A>C		non_coding_transcript_exon_variant	6/13	5
RIOK1	ENST00000484626.1	n.157A>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.917A>C (p.Q306P) alteration is located in exon 10 (coding exon 10) of the RIOK1 gene. This alteration results from a A to C substitution at nucleotide position 917, causing the glutamine (Q) at amino acid position 306 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.38
Sift	Benign	0.032	D
Sift4G	Uncertain	0.038	D
Polyphen		0.98	D
Vest4		0.89
MutPred		0.72		Loss of MoRF binding (P = 0.0381);
MVP		0.42
MPC		0.76
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.94
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1761691891; hg19: chr6-7404713;