19-39173730-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005884.5(PAK4):c.818C>A(p.Pro273His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PAK4 NM_005884.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.595

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14585805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK4	NM_005884.5	c.818C>A	p.Pro273His	missense_variant	5/10	ENST00000360442.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK4	ENST00000360442.8	c.818C>A	p.Pro273His	missense_variant	5/10	5	NM_005884.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182132 Hom.: 0 AF XY: 0.00000994 AC XY: 1 AN XY: 100636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000349

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: 7.02e-7 AC: 1 AN: 1424664 Hom.: 0 Cov.: 34 AF XY: 0.00000142 AC XY: 1 AN XY: 706284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000250

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.818C>A (p.P273H) alteration is located in exon 6 (coding exon 3) of the PAK4 gene. This alteration results from a C to A substitution at nucleotide position 818, causing the proline (P) at amino acid position 273 to be replaced by a histidine (H). 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	0.092
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.56	T;.;T;.;.;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.0060	D;D;T;D;D;D;D
Polyphen		0.0, 0.99, 0.0020	.;B;D;B;B;B;B
Vest4		0.24, 0.24, 0.29, 0.30, 0.19, 0.22
MutPred		0.20		.;.;.;Loss of glycosylation at P273 (P = 0.0372);Loss of glycosylation at P273 (P = 0.0372);.;Loss of glycosylation at P273 (P = 0.0372);
MVP		0.47
MPC		0.32
ClinPred		0.23	T
GERP RS		3.0
Varity_R		0.066
gMVP		0.23

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: rs912960566; hg19: chr19-39664370;