chr14-90872123-T-G

Variant names:

• chr14-90872123-T-G
• rs200886537
• NM_004755.4:c.2360A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004755.4(RPS6KA5):​c.2360A>C​(p.Asp787Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D787V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: RPS6KA5 NM_004755.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 3 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123844326).

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.2360A>C	p.Asp787Ala	missense	Exon 17 of 17	NP_004746.2
	RPS6KA5	NM_001322229.2		c.2339A>C	p.Asp780Ala	missense	Exon 17 of 17	NP_001309158.1
	RPS6KA5	NM_001322236.2		c.2276A>C	p.Asp759Ala	missense	Exon 16 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.2360A>C	p.Asp787Ala	missense	Exon 17 of 17	ENSP00000479667.1	O75582-1
	RPS6KA5	ENST00000886639.1		c.2393A>C	p.Asp798Ala	missense	Exon 17 of 17	ENSP00000556698.1
	RPS6KA5	ENST00000886636.1		c.2339A>C	p.Asp780Ala	missense	Exon 17 of 17	ENSP00000556695.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151760 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74094

African (AFR) AF: 0.00 AC: 0 AN: 41312

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.12
Sift	Uncertain	0.027	D
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.12		Gain of catalytic residue at N789 (P = 0.0764)
MVP		0.33
ClinPred		0.26	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.26
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs200886537; hg19: chr14-91338467;