14-90902945-C-A

Variant names:

• chr14-90902945-C-A
• rs376247617
• NM_004755.4:c.982G>T

Variant summary

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

The NM_004755.4(RPS6KA5):​c.982G>T​(p.Ala328Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A328T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPS6KA5 NM_004755.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.982G>T	p.Ala328Ser	missense	Exon 9 of 17	NP_004746.2
	RPS6KA5	NM_001322229.2		c.982G>T	p.Ala328Ser	missense	Exon 9 of 17	NP_001309158.1
	RPS6KA5	NM_001322236.2		c.898G>T	p.Ala300Ser	missense	Exon 8 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.982G>T	p.Ala328Ser	missense	Exon 9 of 17	ENSP00000479667.1	O75582-1
	RPS6KA5	ENST00000418736.6	TSL:1	c.982G>T	p.Ala328Ser	missense	Exon 9 of 13	ENSP00000402787.2	O75582-2
	RPS6KA5	ENST00000554206.1	TSL:1	n.*359G>T		non_coding_transcript_exon	Exon 9 of 10	ENSP00000450591.1	G3V2D1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457314 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724950

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109448

Other (OTH) AF: 0.0000166 AC: 1 AN: 60182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.17
Sift	Benign	0.079	T
Sift4G	Benign	0.29	T
Polyphen		0.018	B
Vest4		0.71
MutPred		0.36		Gain of catalytic residue at K329 (P = 0.001)
MVP		0.76
ClinPred		0.74	D
GERP RS		5.6
Varity_R		0.12
gMVP		0.41
Mutation Taster		=34/66	disease causing

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: rs376247617; hg19: chr14-91369289;