chr7-6392006-T-G

Position:

• chr7-6392006-T-G

Variant summary

Our verdict is Pathogenic. Variant got 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. Y64C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC1 NM_006908.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.01

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr7-6392007-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333690.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAC1. . Gene score misZ 3.1347 (greater than the threshold 3.09). Trascript score misZ 3.9366 (greater than threshold 3.09). GenCC has associacion of gene with 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 id is 445283.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAC1	NM_006908.5	c.190T>G	p.Tyr64Asp	missense_variant	3/6	ENST00000348035.9
RAC1	NM_018890.4	c.190T>G	p.Tyr64Asp	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAC1	ENST00000348035.9	c.190T>G	p.Tyr64Asp	missense_variant	3/6	1	NM_006908.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 29, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2019

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 v4.3

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;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.77		Gain of disorder (P = 0.0146);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554263626; hg19: chr7-6431637;