17-82032790-G-A

Variant names:

• chr17-82032790-G-A
• rs2043443828
• NM_005052.3:c.187G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_005052.3(RAC3):​c.187G>A​(p.Asp63Asn) 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. 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, single submitter P:2
• Conservation: PhyloP100: 9.59

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, 4 uncertain in NM_005052.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 17-82032790-G-A is Pathogenic according to our data. Variant chr17-82032790-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 871529.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC3	NM_005052.3	c.187G>A	p.Asp63Asn	missense_variant	Exon 3 of 6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.187G>A	p.Asp63Asn	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.187G>A	p.Asp63Asn	missense_variant	Exon 3 of 6	1	NM_005052.3	ENSP00000304283.4
RAC3	ENST00000580965.5	c.55G>A	p.Asp19Asn	missense_variant	Exon 2 of 5	2		ENSP00000463590.1
RAC3	ENST00000584341.1	c.55G>A	p.Asp19Asn	missense_variant	Exon 2 of 5	5		ENSP00000462421.1
RAC3	ENST00000585014.1	n.-88G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 08, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	0.0027	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.88
MutPred		0.51		Loss of disorder (P = 0.1129);.;.;
MVP		0.92
MPC		1.7
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: rs2043443828; hg19: chr17-79990666;