19-39169750-C-T

Position:

• chr19-39169750-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005884.5(PAK4):​c.197C>T​(p.Ala66Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAK4 NM_005884.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3345376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK4	NM_005884.5	c.197C>T	p.Ala66Val	missense_variant	3/10	ENST00000360442.8	NP_005875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK4	ENST00000360442.8	c.197C>T	p.Ala66Val	missense_variant	3/10	5	NM_005884.5	ENSP00000353625.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446432 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 717704

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

May 01, 2024

The c.197C>T (p.A66V) 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 197, causing the alanine (A) at amino acid position 66 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	0.073
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;.;T;T;T;.;.;T
Eigen	Benign	0.087
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;.;D;D;.;.;T;T;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	.;N;N;.;N;N;N;.;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.40	.;.;N;.;N;.;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.43	.;.;T;.;D;.;.;.;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		0.84, 0.97, 0.87	.;P;D;.;P;P;P;.;P
Vest4		0.38, 0.45, 0.45, 0.46, 0.38
MutPred		0.39		.;Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);Loss of disorder (P = 0.0821);
MVP		0.66
MPC		0.74
ClinPred		0.88	D
GERP RS		3.8
Varity_R		0.15
gMVP		0.46

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: rs376845802; hg19: chr19-39660390;