17-82032787-G-A

Position:

• chr17-82032787-G-A

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.184G>A​(p.Glu62Lys) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAC3 NM_005052.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.66

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, 0.982
• PP5: Variant 17-82032787-G-A is Pathogenic according to our data. Variant chr17-82032787-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 425149.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.184G>A	p.Glu62Lys	missense_variant	3/6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.184G>A	p.Glu62Lys	missense_variant	3/6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.184G>A	p.Glu62Lys	missense_variant	3/6	1	NM_005052.3	ENSP00000304283	P1
RAC3	ENST00000580965.5	c.52G>A	p.Glu18Lys	missense_variant	2/5	2		ENSP00000463590
RAC3	ENST00000584341.1	c.52G>A	p.Glu18Lys	missense_variant	2/5	5		ENSP00000462421

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: 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:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 08, 2022

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PP5_very strong;PM2_supporting;PP2_supporting;PP3_supporting -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2020

- -

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	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.94
MutPred		0.90		Gain of ubiquitination at E62 (P = 0.0146);.;.;
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95

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: rs1064797229; hg19: chr17-79990663;