X-111152384-A-G

Variant names:

• chrX-111152384-A-G
• rs16986385
• NM_002578.5:c.431-26A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002578.5(PAK3):​c.431-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,093,025 control chromosomes in the GnomAD database, including 5,383 homozygotes. There are 13,518 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2785 hom., 4678 hem., cov: 23)
  • Exomes 𝑓: 0.033 (2598 hom. 8840 hem.)
• Consequence: PAK3 NM_002578.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.771
• Publications: 3 publications found

Genes affected

PAK3 (HGNC:8592): (p21 (RAC1) activated kinase 3) The protein encoded by this gene is a serine-threonine kinase and forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1. This protein may be necessary for dendritic development and for the rapid cytoskeletal reorganization in dendritic spines associated with synaptic plasticity. Defects in this gene are the cause of a non-syndromic form of X-linked intellectual disability. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2017]

PAK3 Gene-Disease associations (from GenCC):

• corpus callosum, agenesis of

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• intellectual disability, X-linked 30

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant X-111152384-A-G is Benign according to our data. Variant chrX-111152384-A-G is described in ClinVar as Benign. ClinVar VariationId is 1231786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002578.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	NM_002578.5	MANE Select	c.431-26A>G		intron	N/A	NP_002569.1
	PAK3	NM_001128168.3		c.539-26A>G		intron	N/A	NP_001121640.1
	PAK3	NM_001128172.2		c.494-26A>G		intron	N/A	NP_001121644.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	ENST00000372007.10	TSL:1 MANE Select	c.431-26A>G		intron	N/A	ENSP00000361077.4
	PAK3	ENST00000360648.8	TSL:1	c.539-26A>G		intron	N/A	ENSP00000353864.4
	PAK3	ENST00000417227.5	TSL:1	c.494-26A>G		intron	N/A	ENSP00000389172.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 17206 AN: 111012 Hom.: 2784 Cov.: 23

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.0299

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0591

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.0579 AC: 10484 AN: 181087 AF XY: 0.0457

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0353

GnomAD4 exome AF: 0.0329 AC: 32302 AN: 981962 Hom.: 2598 Cov.: 18 AF XY: 0.0302 AC XY: 8840 AN XY: 292790

African (AFR) AF: 0.497 AC: 11484 AN: 23099

American (AMR) AF: 0.0365 AC: 1274 AN: 34903

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 579 AN: 18533

East Asian (EAS) AF: 0.0000338 AC: 1 AN: 29553

South Asian (SAS) AF: 0.0402 AC: 2062 AN: 51335

European-Finnish (FIN) AF: 0.0145 AC: 582 AN: 40276

Middle Eastern (MID) AF: 0.0731 AC: 283 AN: 3869

European-Non Finnish (NFE) AF: 0.0187 AC: 13769 AN: 738199

Other (OTH) AF: 0.0538 AC: 2268 AN: 42195

GnomAD4 genome AF: 0.155 AC: 17232 AN: 111063 Hom.: 2785 Cov.: 23 AF XY: 0.140 AC XY: 4678 AN XY: 33311

African (AFR) AF: 0.490 AC: 14862 AN: 30324

American (AMR) AF: 0.0708 AC: 739 AN: 10443

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 79 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.0314 AC: 83 AN: 2646

European-Finnish (FIN) AF: 0.0104 AC: 63 AN: 6042

Middle Eastern (MID) AF: 0.0602 AC: 13 AN: 216

European-Non Finnish (NFE) AF: 0.0228 AC: 1206 AN: 52984

Other (OTH) AF: 0.123 AC: 187 AN: 1521

Alfa AF: 0.0420 Hom.: 362

Bravo AF: 0.177

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Intellectual disability, X-linked 30 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.42
DANN	Benign	0.35
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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: rs16986385; hg19: chrX-110395612;