14-74910047-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031464.5(RPS6KL1):c.766C>T(p.His256Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPS6KL1 NM_031464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.455

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06497821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KL1	NM_031464.5	c.766C>T	p.His256Tyr	missense_variant	8/12	ENST00000557413.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KL1	ENST00000557413.6	c.766C>T	p.His256Tyr	missense_variant	8/12	5	NM_031464.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460634 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jun 27, 2023

The c.766C>T (p.H256Y) alteration is located in exon 7 (coding exon 6) of the RPS6KL1 gene. This alteration results from a C to T substitution at nucleotide position 766, causing the histidine (H) at amino acid position 256 to be replaced by a tyrosine (Y). 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	0.079
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	2.1
Dann	Benign	0.85
DEOGEN2	Benign	0.0018	T;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T;.;.
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
REVEL	Benign	0.061
Sift4G	Benign	0.54	T;T;T
Polyphen		0.35	B;B;B
Vest4		0.21
MutPred		0.35		Gain of phosphorylation at H256 (P = 0.0333);Gain of phosphorylation at H256 (P = 0.0333);Gain of phosphorylation at H256 (P = 0.0333);
MVP		0.58
MPC		0.26
ClinPred		0.077	T
GERP RS		-5.6
Varity_R		0.030
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs776026626; hg19: chr14-75376750;