X-111123171-G-T

Variant names:

• chrX-111123171-G-T
• NM_002578.5:c.68G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002578.5(PAK3):​c.68G>T​(p.Arg23Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000642 in 1,090,032 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.68G>T	p.Arg23Leu	missense_variant	Exon 5 of 18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.68G>T	p.Arg23Leu	missense_variant	Exon 5 of 18	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000642 AC: 7 AN: 1090032 Hom.: 0 Cov.: 28 AF XY: 0.00000843 AC XY: 3 AN XY: 355682

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: 0.00000839

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T;.;.;.;T;.;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;.;L;L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.032	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;P;.;B;P;B
Vest4		0.66
MutPred		0.17		Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);Loss of catalytic residue at R23 (P = 0.039);
MVP		0.97
MPC		1.4
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.66
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-110366399;