chr14-74907529-G-C

Variant names:

• chr14-74907529-G-C
• rs1290464834
• NM_031464.5:c.1445C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031464.5(RPS6KL1):​c.1445C>G​(p.Ala482Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KL1 NM_031464.5 missense, splice_region
• Scores: Splicing: ADA: 0.9660
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.96

Genes affected

RPS6KL1 (HGNC:20222): (ribosomal protein S6 kinase like 1) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in ribosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KL1	NM_031464.5	c.1445C>G	p.Ala482Gly	missense_variant, splice_region_variant	Exon 11 of 12	ENST00000557413.6	NP_113652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KL1	ENST00000557413.6	c.1445C>G	p.Ala482Gly	missense_variant, splice_region_variant	Exon 11 of 12	5	NM_031464.5	ENSP00000450567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0087	T;T;.;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L;L;.;.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	.;N;D;N;N
REVEL	Benign	0.19
Sift	Benign	0.042	.;D;D;T;D
Sift4G	Benign	0.43	T;T;D;T;T
Polyphen		0.24	B;B;.;.;B
Vest4		0.47
MutPred		0.51		Gain of disorder (P = 0.0623);Gain of disorder (P = 0.0623);.;.;Gain of disorder (P = 0.0623);
MVP		0.66
MPC		0.30
ClinPred		0.69	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.64
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: rs1290464834; hg19: chr14-75374232;