X-111216599-C-G

Variant names:

• chrX-111216599-C-G
• rs10521535
• NM_002578.5:c.1545+41C>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.1545+41C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 1,071,314 control chromosomes in the GnomAD database, including 809 homozygotes. There are 9,591 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (303 hom., 1791 hem., cov: 23)
  • Exomes 𝑓: 0.029 (506 hom. 7800 hem.)
• Consequence: PAK3 NM_002578.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.132
• Publications: 5 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=-0.88).
• BP6: Variant X-111216599-C-G is Benign according to our data. Variant chrX-111216599-C-G is described in ClinVar as Benign. ClinVar VariationId is 1244665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.1545+41C>G		intron_variant	Intron 17 of 17	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.1545+41C>G		intron_variant	Intron 17 of 17	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 6706 AN: 111351 Hom.: 303 Cov.: 23

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00582

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.0129

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.0177

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.0921

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0662

GnomAD2 exomes AF: 0.0312 AC: 5691 AN: 182268 AF XY: 0.0273

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.000579

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.0276

Gnomad OTH exome AF: 0.0364

GnomAD4 exome AF: 0.0295 AC: 28303 AN: 959913 Hom.: 506 Cov.: 18 AF XY: 0.0296 AC XY: 7800 AN XY: 263197

African (AFR) AF: 0.154 AC: 3653 AN: 23765

American (AMR) AF: 0.0248 AC: 868 AN: 34976

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 331 AN: 18454

East Asian (EAS) AF: 0.000474 AC: 14 AN: 29540

South Asian (SAS) AF: 0.0163 AC: 832 AN: 51133

European-Finnish (FIN) AF: 0.0146 AC: 588 AN: 40139

Middle Eastern (MID) AF: 0.0755 AC: 288 AN: 3814

European-Non Finnish (NFE) AF: 0.0283 AC: 20251 AN: 716696

Other (OTH) AF: 0.0357 AC: 1478 AN: 41396

GnomAD4 genome AF: 0.0604 AC: 6727 AN: 111401 Hom.: 303 Cov.: 23 AF XY: 0.0533 AC XY: 1791 AN XY: 33627

African (AFR) AF: 0.151 AC: 4607 AN: 30536

American (AMR) AF: 0.0344 AC: 361 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 34 AN: 2635

East Asian (EAS) AF: 0.00113 AC: 4 AN: 3546

South Asian (SAS) AF: 0.0177 AC: 47 AN: 2649

European-Finnish (FIN) AF: 0.0117 AC: 70 AN: 5980

Middle Eastern (MID) AF: 0.0963 AC: 21 AN: 218

European-Non Finnish (NFE) AF: 0.0279 AC: 1480 AN: 53138

Other (OTH) AF: 0.0647 AC: 99 AN: 1530

Alfa AF: 0.0409 Hom.: 298

Bravo AF: 0.0667

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.29
DANN	Benign	0.54
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs10521535; hg19: chrX-110459827;