rs1554263326

Variant names:

• chr7-6387229-G-A
• rs1554263326
• NM_006908.5:c.53G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-6387229-G-A
• chr7-6387229-G-C
• chr7-6387229-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_006908.5(RAC1):​c.53G>A​(p.Cys18Tyr) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC1 NM_006908.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.85

Genes affected

RAC1 (HGNC:9801): (Rac family small GTPase 1) 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RAC1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.1347 (above the threshold of 3.09). Trascript score misZ: 3.9366 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 48.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 7-6387229-G-A is Pathogenic according to our data. Variant chr7-6387229-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 445280.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5	c.53G>A	p.Cys18Tyr	missense_variant	Exon 2 of 6	ENST00000348035.9	NP_008839.2
RAC1	NM_018890.4	c.53G>A	p.Cys18Tyr	missense_variant	Exon 2 of 7		NP_061485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9	c.53G>A	p.Cys18Tyr	missense_variant	Exon 2 of 6	1	NM_006908.5	ENSP00000258737.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 48 Pathogenic:1

Dec 09, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with the prevention of GTP-mediated activation of RAC1 and LTP induction (PMID: 30042656); 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: 28886345, 27479843, 30042656) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-9.7	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.91
MutPred		0.84		Loss of catalytic residue at L19 (P = 0.0226);Loss of catalytic residue at L19 (P = 0.0226);
MVP		0.93
MPC		4.1
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.98
gMVP		1.0

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: rs1554263326; hg19: chr7-6426860; COSMIC: COSV61822452; COSMIC: COSV61822452;