chr7-6392006-T-G

Variant names:

• chr7-6392006-T-G
• rs1554263626
• NM_006908.5:c.190T>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_006908.5(RAC1):​c.190T>G​(p.Tyr64Asp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y64H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC1 NM_006908.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.01
• Publications: 2 publications found

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]

RAC1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 48

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Illumina, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006908.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-6392006-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2431922.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.943
• PP5: Variant 7-6392006-T-G is Pathogenic according to our data. Variant chr7-6392006-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 445283.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006908.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC1	NM_006908.5	MANE Select	c.190T>G	p.Tyr64Asp	missense	Exon 3 of 6	NP_008839.2
	RAC1	NM_018890.4		c.190T>G	p.Tyr64Asp	missense	Exon 3 of 7	NP_061485.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC1	ENST00000348035.9	TSL:1 MANE Select	c.190T>G	p.Tyr64Asp	missense	Exon 3 of 6	ENSP00000258737.7
	RAC1	ENST00000356142.4	TSL:1	c.190T>G	p.Tyr64Asp	missense	Exon 3 of 7	ENSP00000348461.4
	RAC1	ENST00000488373.5	TSL:1	n.421T>G		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 48 Pathogenic:2

Mar 29, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 03, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 28886345). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with RAC1 related disorder (ClinVar ID: VCV000445283 /PMID: 28886345). Different missense changes at the same codon (p.Tyr64Cys, p.Tyr64His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001333690, VCV002431922 /PMID: 35139179 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:1

Sep 04, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; in vitro studies demonstrate that Y64D results in altered changes in cellular morphology and reduced binding to protein kinase A (Chang et al., 2011; Reijnders et al., 2017); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28886345, 22163037, 28135719, 30544910)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.77		Gain of disorder (P = 0.0146)
MVP		0.98
MPC		5.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554263626; hg19: chr7-6431637;