1-22078579-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001791.4(CDC42):c.101C>A(p.Pro34Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDC42 NM_001791.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.33

Genes affected

CDC42 (HGNC:1736): (cell division cycle 42) The protein encoded by this gene is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression. This protein is highly similar to Saccharomyces cerevisiae Cdc 42, and is able to complement the yeast cdc42-1 mutant. The product of oncogene Dbl was reported to specifically catalyze the dissociation of GDP from this protein. This protein could regulate actin polymerization through its direct binding to Neural Wiskott-Aldrich syndrome protein (N-WASP), which subsequently activates Arp2/3 complex. Alternative splicing of this gene results in multiple transcript variants. Pseudogenes of this gene have been identified on chromosomes 3, 4, 5, 7, 8 and 20. [provided by RefSeq, Apr 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Cell division control protein 42 homolog (size 187) in uniprot entity CDC42_HUMAN there are 33 pathogenic changes around while only 0 benign (100%) in NM_001791.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 1-22078579-C-A is Pathogenic according to our data. Variant chr1-22078579-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1013509.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC42	NM_001791.4	c.101C>A	p.Pro34Gln	missense_variant	2/6	ENST00000656825.1
CDC42	NM_001039802.2	c.101C>A	p.Pro34Gln	missense_variant	3/7
CDC42	NM_044472.3	c.101C>A	p.Pro34Gln	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC42	ENST00000656825.1	c.101C>A	p.Pro34Gln	missense_variant	2/6		NM_001791.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 2 AN: 1453244 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 722566

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CDC42-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2023

The CDC42 c.101C>A variant is predicted to result in the amino acid substitution p.Pro34Gln. his variant has been reported as de novo in two patients with pancytopenia (Patient 17-5428 in Table S1 in Monies. 2019. PubMed ID: 31130284; Asiri et al. 2021. PubMed ID: 33672558). Functional analysis of skin fibroblasts isolated from the patient reported in Asiri et al. showed reduced growth and motility (Asiri et al. 2021. PubMed ID: 33672558). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

- -

Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 30, 2021

ACMG classification criteria: PS3 supporting, PS4 supporting, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		1.0	.;D;D;D;.
Vest4		0.82, 0.78
MutPred		0.79		Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);Gain of catalytic residue at P34 (P = 0.0393);
MVP		0.89
MPC		3.2
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1645575465; hg19: chr1-22405072; COSMIC: COSV100212550;