chr17-82032779-C-G

Variant names:

• chr17-82032779-C-G
• rs1379395211
• NM_005052.3:c.176C>G

Variant summary

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

The NM_005052.3(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 NM_005052.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 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, 5 uncertain in NM_005052.3
• 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: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=4}. Variant chr17-82032779-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.176C>G	p.Ala59Gly	missense_variant	Exon 3 of 6	1	NM_005052.3	ENSP00000304283.4
RAC3	ENST00000580965.5	c.44C>G	p.Ala15Gly	missense_variant	Exon 2 of 5	2		ENSP00000463590.1
RAC3	ENST00000584341.1	c.44C>G	p.Ala15Gly	missense_variant	Exon 2 of 5	5		ENSP00000462421.1
RAC3	ENST00000585014.1	n.-99C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies Pathogenic:4 Uncertain:1

Sep 12, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 08, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2020

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jun 29, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.64; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RAC3 related disorder (ClinVar ID: VCV000488059). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29276006). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Mar 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 01, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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;.;.
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;