rs751962517

Variant names:

• chr19-39169651-C-T
• rs751962517
• NM_005884.5:c.98C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-39169651-C-T
• chr19-39169651-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005884.5(PAK4):​c.98C>T​(p.Thr33Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PAK4 NM_005884.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66
• Publications: 1 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 10 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.98C>T	p.Thr33Met	missense	Exon 3 of 10	NP_005875.1	O96013-1
	PAK4	NM_001014831.3		c.98C>T	p.Thr33Met	missense	Exon 4 of 11	NP_001014831.1	O96013-1
	PAK4	NM_001014832.2		c.98C>T	p.Thr33Met	missense	Exon 2 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.98C>T	p.Thr33Met	missense	Exon 3 of 10	ENSP00000353625.3	O96013-1
	PAK4	ENST00000358301.7	TSL:1	c.98C>T	p.Thr33Met	missense	Exon 2 of 9	ENSP00000351049.2	O96013-1
	PAK4	ENST00000593690.5	TSL:1	c.98C>T	p.Thr33Met	missense	Exon 4 of 11	ENSP00000469413.1	O96013-1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000448 AC: 11 AN: 245394 AF XY: 0.0000598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460408 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726538

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111836

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000660 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	0.19
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.55
MutPred		0.54		Loss of phosphorylation at T33 (P = 0.0376)
MVP		0.78
MPC		0.86
ClinPred		0.53	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.67
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs751962517; hg19: chr19-39660291;