rs1390290077

Variant names:

• chrX-111147767-C-A
• rs1390290077
• NM_002578.5:c.307C>A

Variant summary

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

The NM_002578.5(PAK3):​c.307C>A​(p.Gln103Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,093,076 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 1 publications found

Genes affected

PAK3 (HGNC:8592): (p21 (RAC1) activated kinase 3) The protein encoded by this gene is a serine-threonine kinase and forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1. This protein may be necessary for dendritic development and for the rapid cytoskeletal reorganization in dendritic spines associated with synaptic plasticity. Defects in this gene are the cause of a non-syndromic form of X-linked intellectual disability. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2017]

PAK3 Gene-Disease associations (from GenCC):

• corpus callosum, agenesis of

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• intellectual disability, X-linked 30

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

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_002578.5. 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
	PAK3	NM_002578.5	MANE Select	c.307C>A	p.Gln103Lys	missense	Exon 7 of 18	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.415C>A	p.Gln139Lys	missense	Exon 9 of 20	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.370C>A	p.Gln124Lys	missense	Exon 4 of 15	NP_001121644.1	O75914-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	ENST00000372007.10	TSL:1 MANE Select	c.307C>A	p.Gln103Lys	missense	Exon 7 of 18	ENSP00000361077.4	O75914-2
	PAK3	ENST00000360648.8	TSL:1	c.415C>A	p.Gln139Lys	missense	Exon 5 of 16	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.370C>A	p.Gln124Lys	missense	Exon 4 of 15	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183164 AF XY: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1093076 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 358696

African (AFR) AF: 0.00 AC: 0 AN: 26292

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19340

East Asian (EAS) AF: 0.00 AC: 0 AN: 30164

South Asian (SAS) AF: 0.00 AC: 0 AN: 54021

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 837484

Other (OTH) AF: 0.00 AC: 0 AN: 45929

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.60
Sift	Benign	0.11	T
Sift4G	Benign	0.31	T
Polyphen		0.071	B
Vest4		0.58
MutPred		0.49		Gain of methylation at Q118 (P = 0.0231)
MVP		0.99
MPC		1.5
ClinPred		0.36	T
GERP RS		5.7
Varity_R		0.84
gMVP		0.80
Mutation Taster		=70/30	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: rs1390290077; hg19: chrX-110390995;