rs1554263626

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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

Scores

14
3
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.01
Variant links:
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]

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ACMG classification

Classification made for transcript

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
RAC1NM_006908.5 linkuse as main transcriptc.190T>G p.Tyr64Asp missense_variant 3/6 ENST00000348035.9
RAC1NM_018890.4 linkuse as main transcriptc.190T>G p.Tyr64Asp missense_variant 3/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RAC1ENST00000348035.9 linkuse as main transcriptc.190T>G p.Tyr64Asp missense_variant 3/61 NM_006908.5 P1P63000-1

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
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 48 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 29, 2023- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 04, 2019Published 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554263626; hg19: chr7-6431637; API