17-82032779-C-G

Position:

• chr17-82032779-C-G

Variant summary

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

The ENST00000306897.9(RAC3):​c.176C>G​(p.Ala59Gly) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAC3 ENST00000306897.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.82

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000306897.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 17-82032779-C-G is Pathogenic according to our data. Variant chr17-82032779-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488059.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=3}. Variant chr17-82032779-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAC3	NM_005052.3	c.176C>G	p.Ala59Gly	missense_variant	3/6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.176C>G	p.Ala59Gly	missense_variant	3/6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.176C>G	p.Ala59Gly	missense_variant	3/6	1	NM_005052.3	ENSP00000304283.4
RAC3	ENST00000580965.5	c.44C>G	p.Ala15Gly	missense_variant	2/5	2		ENSP00000463590.1
RAC3	ENST00000584341.1	c.44C>G	p.Ala15Gly	missense_variant	2/5	5		ENSP00000462421.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 02, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 08, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 12, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2024

Published functional studies demonstrate a damaging effect by increasing binding to Rac Binding Regions and increasing transcriptional activation of downstream signaling (PMID: 35851598); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35851598, 35047859, 29276006) -

Distal shortening of limbs Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jun 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;.;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.57	P;.;.
Vest4		0.76
MutPred		0.68		Gain of relative solvent accessibility (P = 0.0023);.;.;
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		3.8
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: rs1379395211; hg19: chr17-79990655;