14-74907529-G-T

Variant names:

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

Variant summary

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

The NM_031464.5(RPS6KL1):​c.1445C>A​(p.Ala482Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,200 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RPS6KL1 NM_031464.5 missense, splice_region
• Scores: Splicing: ADA: 0.9786
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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>A	p.Ala482Glu	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>A	p.Ala482Glu	missense_variant, splice_region_variant	Exon 11 of 12	5	NM_031464.5	ENSP00000450567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000223 AC: 4 AN: 179642 Hom.: 0 AF XY: 0.0000210 AC XY: 2 AN XY: 95460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419200 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1445C>A (p.A482E) alteration is located in exon 10 (coding exon 9) of the RPS6KL1 gene. This alteration results from a C to A substitution at nucleotide position 1445, causing the alanine (A) at amino acid position 482 to be replaced by a glutamic acid (E). 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	Benign	0.33
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0072	T;T;.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;D;D;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.93	L;L;.;.;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	.;N;D;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.014	.;D;D;T;D
Sift4G	Benign	0.075	T;T;D;T;T
Polyphen		0.61	P;P;.;.;P
Vest4		0.63
MutPred		0.44		Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);.;.;Gain of disorder (P = 0.0216);
MVP		0.70
MPC		0.49
ClinPred		0.41	T
GERP RS		5.7
Varity_R		0.33
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.0		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;