rs864309721

Positions:

• chr1-22086451-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001791.4(CDC42):​c.191A>G​(p.Tyr64Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y64S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC42 NM_001791.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.10

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a modified_residue Phosphotyrosine; by SRC (size 0) in uniprot entity CDC42_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001791.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-22086451-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2664644.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 1-22086451-A-G is Pathogenic according to our data. Variant chr1-22086451-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-22086451-A-G is described in Lovd as [Pathogenic]. Variant chr1-22086451-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC42	NM_001791.4	c.191A>G	p.Tyr64Cys	missense_variant	4/6	ENST00000656825.1
CDC42	NM_001039802.2	c.191A>G	p.Tyr64Cys	missense_variant	5/7
CDC42	NM_044472.3	c.191A>G	p.Tyr64Cys	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC42	ENST00000656825.1	c.191A>G	p.Tyr64Cys	missense_variant	4/6		NM_001791.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	CDC42: PS2:Very Strong, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Published functional studies demonstrate a damaging effect on GTPase activity and protein binding (Martinelli et al., 2018); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33405195, 34624555, 30872706, 26386261, 26708094, 29394990, 29335451, 31953712, 33083013, 32819561, 34504210) -

Abnormal facial shape;C0850715:Abnormality of blood and blood-forming tissues;C1859778:Postnatal growth retardation;C4021753:Abnormality of the immune system;C4022737:Neurodevelopmental abnormality Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;.;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
Polyphen		1.0	.;D;D;D;.
Vest4		0.93, 0.90
MVP		0.92
MPC		2.6
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
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: rs864309721; hg19: chr1-22412944;