Variant 19-39173652-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005884.5(PAK4):c.740C>T(p.Ser247Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 1,580,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PAK4
NM_005884.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.158

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05756873).

BS2

High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK4	NM_005884.5 linkuse as main transcript	c.740C>T	p.Ser247Phe	missense_variant	5/10	ENST00000360442.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK4	ENST00000360442.8 linkuse as main transcript	c.740C>T	p.Ser247Phe	missense_variant	5/10	5	NM_005884.5	P1	O96013-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000478

GnomAD3 exomes

AF:

0.0000373

AC:

AN:

214528

Hom.:

AF XY:

0.0000169

AC XY:

AN XY:

118056

show subpopulations

Gnomad AFR exome

AF:

0.000610

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000161

AC:

AN:

1428464

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

706754

show subpopulations

Gnomad4 AFR exome

AF:

0.000520

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:

0.00000366

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.000132

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.000411

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000584

AC:

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

Nov 14, 2023

The c.740C>T (p.S247F) alteration is located in exon 6 (coding exon 3) of the PAK4 gene. This alteration results from a C to T substitution at nucleotide position 740, causing the serine (S) at amino acid position 247 to be replaced by a phenylalanine (F). 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

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Benign

0.94

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.54

T;.;T;.;.;T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.058

T;T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationTaster

Benign

0.82

N;N;N;N

PrimateAI

Uncertain

0.75

Sift4G

Uncertain

0.032

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

Polyphen

0.037, 0.99, 0.089

.;B;D;B;B;B;B

Vest4

0.37, 0.38, 0.35, 0.36, 0.38, 0.33

MutPred

0.28

.;.;.;Loss of glycosylation at S247 (P = 9e-04);Loss of glycosylation at S247 (P = 9e-04);.;Loss of glycosylation at S247 (P = 9e-04);

MVP

0.75

MPC

0.31

ClinPred

0.047

GERP RS

3.0

Varity_R

0.057

gMVP

0.25

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