chr19-39173087-C-A

Variant names:

• chr19-39173087-C-A
• rs1444151090
• NM_005884.5:c.374C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005884.5(PAK4):​c.374C>A​(p.Ala125Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,548,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PAK4 NM_005884.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08039793).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005884.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK4	NM_005884.5	MANE Select	c.374C>A	p.Ala125Asp	missense	Exon 4 of 10	NP_005875.1	O96013-1
	PAK4	NM_001014831.3		c.374C>A	p.Ala125Asp	missense	Exon 5 of 11	NP_001014831.1	O96013-1
	PAK4	NM_001014832.2		c.374C>A	p.Ala125Asp	missense	Exon 3 of 9	NP_001014832.1	O96013-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK4	ENST00000360442.8	TSL:5 MANE Select	c.374C>A	p.Ala125Asp	missense	Exon 4 of 10	ENSP00000353625.3	O96013-1
	PAK4	ENST00000358301.7	TSL:1	c.374C>A	p.Ala125Asp	missense	Exon 3 of 9	ENSP00000351049.2	O96013-1
	PAK4	ENST00000593690.5	TSL:1	c.374C>A	p.Ala125Asp	missense	Exon 5 of 11	ENSP00000469413.1	O96013-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

GnomAD2 exomes AF: 0.00000681 AC: 1 AN: 146768 AF XY: 0.0000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000430 AC: 6 AN: 1396264 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 688608

African (AFR) AF: 0.00 AC: 0 AN: 31528

American (AMR) AF: 0.000140 AC: 5 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078528

Other (OTH) AF: 0.0000173 AC: 1 AN: 57844

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.36
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.29
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.079
Sift	Benign	0.63	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.24		Gain of solvent accessibility (P = 0.0156)
MVP		0.33
MPC		0.35
ClinPred		0.022	T
GERP RS		1.8
Varity_R		0.092
gMVP		0.17
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1444151090; hg19: chr19-39663727;