19-39169637-C-T

Variant names:

• chr19-39169637-C-T
• rs75096376
• NM_005884.5:c.84C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_005884.5(PAK4):​c.84C>T​(p.His28His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,613,558 control chromosomes in the GnomAD database, including 820 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (66 hom., cov: 31)
  • Exomes 𝑓: 0.030 (754 hom.)
• Consequence: PAK4 NM_005884.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 3 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3193/152250) while in subpopulation NFE AF = 0.0285 (1941/67992). AF 95% confidence interval is 0.0275. There are 66 homozygotes in GnomAd4. There are 1659 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3193 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.84C>T	p.His28His	synonymous	Exon 3 of 10	NP_005875.1	O96013-1
	PAK4	NM_001014831.3		c.84C>T	p.His28His	synonymous	Exon 4 of 11	NP_001014831.1	O96013-1
	PAK4	NM_001014832.2		c.84C>T	p.His28His	synonymous	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.84C>T	p.His28His	synonymous	Exon 3 of 10	ENSP00000353625.3	O96013-1
	PAK4	ENST00000358301.7	TSL:1	c.84C>T	p.His28His	synonymous	Exon 2 of 9	ENSP00000351049.2	O96013-1
	PAK4	ENST00000593690.5	TSL:1	c.84C>T	p.His28His	synonymous	Exon 4 of 11	ENSP00000469413.1	O96013-1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3192 AN: 152132 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0197

GnomAD2 exomes AF: 0.0248 AC: 6161 AN: 248744 AF XY: 0.0258

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.00878

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.0300 AC: 43809 AN: 1461308 Hom.: 754 Cov.: 33 AF XY: 0.0302 AC XY: 21945 AN XY: 726964

African (AFR) AF: 0.00367 AC: 123 AN: 33480

American (AMR) AF: 0.00955 AC: 427 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 325 AN: 26114

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39694

South Asian (SAS) AF: 0.0321 AC: 2767 AN: 86248

European-Finnish (FIN) AF: 0.0517 AC: 2739 AN: 52998

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5762

European-Non Finnish (NFE) AF: 0.0321 AC: 35711 AN: 1111922

Other (OTH) AF: 0.0260 AC: 1573 AN: 60384

GnomAD4 genome AF: 0.0210 AC: 3193 AN: 152250 Hom.: 66 Cov.: 31 AF XY: 0.0223 AC XY: 1659 AN XY: 74418

African (AFR) AF: 0.00515 AC: 214 AN: 41568

American (AMR) AF: 0.0114 AC: 174 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5166

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4826

European-Finnish (FIN) AF: 0.0596 AC: 633 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1941 AN: 67992

Other (OTH) AF: 0.0194 AC: 41 AN: 2108

Alfa AF: 0.0149 Hom.: 10

Bravo AF: 0.0166

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0279

EpiControl AF: 0.0264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.081
DANN	Benign	0.81
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

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: rs75096376; hg19: chr19-39660277;