chr14-91060373-C-A

Variant names:

• chr14-91060373-C-A
• rs749352681
• NM_004755.4:c.62G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004755.4(RPS6KA5):​c.62G>T​(p.Gly21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,354,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RPS6KA5 NM_004755.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.646
• Publications: 0 publications found

Genes affected

RPS6KA5 (HGNC:10434): (ribosomal protein S6 kinase A5) Enables ATP binding activity and protein serine/threonine kinase activity. Involved in several processes, including histone-serine phosphorylation; positive regulation of histone modification; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DGLUCY (HGNC:20498): (D-glutamate cyclase) Predicted to enable D-glutamate cyclase activity. Predicted to be involved in glutamate metabolic process. Predicted to be located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.117726564).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA5	NM_004755.4	MANE Select	c.62G>T	p.Gly21Val	missense	Exon 1 of 17	NP_004746.2
	RPS6KA5	NM_001322229.2		c.62G>T	p.Gly21Val	missense	Exon 1 of 17	NP_001309158.1
	RPS6KA5	NM_001322236.2		c.62G>T	p.Gly21Val	missense	Exon 1 of 16	NP_001309165.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA5	ENST00000614987.5	TSL:1 MANE Select	c.62G>T	p.Gly21Val	missense	Exon 1 of 17	ENSP00000479667.1	O75582-1
	RPS6KA5	ENST00000418736.6	TSL:1	c.62G>T	p.Gly21Val	missense	Exon 1 of 13	ENSP00000402787.2	O75582-2
	RPS6KA5	ENST00000554206.1	TSL:1	n.62G>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000450591.1	G3V2D1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000114 AC: 2 AN: 175326 AF XY: 0.0000202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000255

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 14 AN: 1354628 Hom.: 0 Cov.: 31 AF XY: 0.0000119 AC XY: 8 AN XY: 671738

African (AFR) AF: 0.00 AC: 0 AN: 28486

American (AMR) AF: 0.00 AC: 0 AN: 35272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23392

East Asian (EAS) AF: 0.00 AC: 0 AN: 32028

South Asian (SAS) AF: 0.00 AC: 0 AN: 73500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.0000133 AC: 14 AN: 1054010

Other (OTH) AF: 0.00 AC: 0 AN: 54776

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000560 Hom.: 0

ExAC AF: 0.00000837 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.65
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.082
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.13	T
Polyphen		0.053	B
Vest4		0.20
MutPred		0.39		Gain of catalytic residue at G19 (P = 0.0016)
MVP		0.66
ClinPred		0.15	T
GERP RS		0.20
PromoterAI		0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.68
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs749352681; hg19: chr14-91526717;