chrX-111123295-C-T

Variant names:

• chrX-111123295-C-T
• rs767162489
• NM_002578.5:c.175+17C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_002578.5(PAK3):​c.175+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,168,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 6 hem.)
• Consequence: PAK3 NM_002578.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.110
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant X-111123295-C-T is Benign according to our data. Variant chrX-111123295-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1907505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	NM_002578.5	MANE Select	c.175+17C>T		intron	N/A	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.175+17C>T		intron	N/A	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.175+17C>T		intron	N/A	NP_001121644.1	O75914-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	ENST00000372007.10	TSL:1 MANE Select	c.175+17C>T		intron	N/A	ENSP00000361077.4	O75914-2
	PAK3	ENST00000360648.8	TSL:1	c.175+17C>T		intron	N/A	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.175+17C>T		intron	N/A	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112322 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

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: 0.0000166 AC: 3 AN: 180915 AF XY: 0.00

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000724

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 13 AN: 1055709 Hom.: 0 Cov.: 25 AF XY: 0.0000184 AC XY: 6 AN XY: 325655

African (AFR) AF: 0.0000781 AC: 2 AN: 25614

American (AMR) AF: 0.00 AC: 0 AN: 35122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19093

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30040

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53059

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3935

European-Non Finnish (NFE) AF: 0.00000995 AC: 8 AN: 803631

Other (OTH) AF: 0.0000223 AC: 1 AN: 44744

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112322 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34498

African (AFR) AF: 0.0000323 AC: 1 AN: 30945

American (AMR) AF: 0.0000939 AC: 1 AN: 10652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6119

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53269

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.9
DANN	Benign	0.79
PhyloP100		-0.11
PromoterAI		0.011	Neutral

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: rs767162489; hg19: chrX-110366523;