19-39173152-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005884.5(PAK4):c.439G>A(p.Gly147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,541,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: PAK4 NM_005884.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.638

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007831365).
• BP6: Variant 19-39173152-G-A is Benign according to our data. Variant chr19-39173152-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3208044.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK4	NM_005884.5	c.439G>A	p.Gly147Ser	missense_variant	4/10	ENST00000360442.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK4	ENST00000360442.8	c.439G>A	p.Gly147Ser	missense_variant	4/10	5	NM_005884.5	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000370 AC: 52 AN: 140650 Hom.: 0 AF XY: 0.000356 AC XY: 27 AN XY: 75918

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.000514

Gnomad EAS exome AF: 0.0000933

Gnomad SAS exome AF: 0.0000914

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000212 AC: 295 AN: 1389640 Hom.: 1 Cov.: 33 AF XY: 0.000225 AC XY: 154 AN XY: 684064

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000824

Gnomad4 ASJ exome AF: 0.000242

Gnomad4 EAS exome AF: 0.000169

Gnomad4 SAS exome AF: 0.0000890

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000452

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74460

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000288 Hom.: 1

Bravo AF: 0.000472

ESP6500AA AF: 0.000282 AC: 1

ESP6500EA AF: 0.000138 AC: 1

ExAC AF: 0.000109 AC: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	1.7
Dann	Benign	0.96
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.040	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.51	N;.;N
REVEL	Benign	0.082
Sift	Benign	0.86	T;.;T
Sift4G	Benign	0.83	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.12
MVP		0.49
MPC		0.22
ClinPred		0.0023	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.047
gMVP		0.11

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

Other links and lift over

dbSNP: rs199622580; hg19: chr19-39663792;