Variant 19-39169591-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005884.5(PAK4):c.38C>T(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PAK4
NM_005884.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

PAK4 (HGNC:16059): (p21 (RAC1) activated kinase 4) PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PAK4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK4	NM_005884.5 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	3/10	ENST00000360442.8	NP_005875.1	O96013-1A0A024R0J1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK4	ENST00000360442.8 linkuse as main transcript	c.38C>T	p.Ala13Val	missense_variant	3/10	5	NM_005884.5	ENSP00000353625.3		O96013-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250042

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135376

show subpopulations

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 SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461492

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.38C>T (p.A13V) alteration is located in exon 4 (coding exon 1) of the PAK4 gene. This alteration results from a C to T substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

.;.;.;D;D;D;.;.;D

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;.;D;D;.;.;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.6

.;M;M;.;M;M;M;.;M

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.7

.;.;N;.;N;.;.;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.49

.;.;T;.;D;.;.;.;D

Sift4G

Uncertain

0.026

D;T;T;T;T;T;T;T;T

Polyphen

1.0, 0.99

.;D;D;.;D;D;D;.;D

Vest4

0.55, 0.57, 0.56, 0.58, 0.56, 0.58

MVP

0.78

MPC

0.84

ClinPred

0.85

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over