17-82032794-A-G

Position:

• chr17-82032794-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_005052.3(RAC3):​c.191A>G​(p.Tyr64Cys) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAC3 NM_005052.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.79

Genes affected

RAC3 (HGNC:9803): (Rac family small GTPase 3) The protein encoded by this gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 17-82032794-A-G is Pathogenic according to our data. Variant chr17-82032794-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 982386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAC3	NM_005052.3	c.191A>G	p.Tyr64Cys	missense_variant	3/6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.191A>G	p.Tyr64Cys	missense_variant	3/6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.191A>G	p.Tyr64Cys	missense_variant	3/6	1	NM_005052.3	ENSP00000304283	P1
RAC3	ENST00000580965.5	c.59A>G	p.Tyr20Cys	missense_variant	2/5	2		ENSP00000463590
RAC3	ENST00000584341.1	c.59A>G	p.Tyr20Cys	missense_variant	2/5	5		ENSP00000462421

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Apr 09, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 08, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.4	H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.4	D;.;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.80		Loss of phosphorylation at Y64 (P = 0.0255);.;.;
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92

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: rs2043443851; hg19: chr17-79990670;