rs1554263625

Variant names:

• chr7-6391967-G-A
• rs1554263625
• NM_006908.5:c.151G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-6391967-G-A
• chr7-6391967-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_006908.5(RAC1):​c.151G>A​(p.Val51Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V51L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAC1 NM_006908.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0
• Publications: 3 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 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr7-6391967-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 445285.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.
• PP5: Variant 7-6391967-G-A is Pathogenic according to our data. Variant chr7-6391967-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 445284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5	c.151G>A	p.Val51Met	missense_variant	Exon 3 of 6	ENST00000348035.9	NP_008839.2
RAC1	NM_018890.4	c.151G>A	p.Val51Met	missense_variant	Exon 3 of 7		NP_061485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9	c.151G>A	p.Val51Met	missense_variant	Exon 3 of 6	1	NM_006908.5	ENSP00000258737.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 21, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RAC1 gene demonstrated a sequence change, c.151G>A, in exon 3 that results in an amino acid change, p.Val51Met. Based on this analysis the c.151G>A sequence change was found to be absent in both parents and is therefore a de novo change in this patient. This sequence change is absent from the gnomAD database. This pathogenic sequence change has previously been described in the de novo state in a patient with RAC1-related intellectual disability (PMID: 28886345). PMID: 28886345, also identified a patient with a different de novo variant affecting the same nucleotide, c.151G>C (p.Val51Leu). Both patients had intellectual disabilities and macrocephaly. Functional analysis of the p.Val51Met in fibroblasts showed inconclusive results regarding the functional effect of this variant (Reijnders et al., 2017). The p.Val51Met change affects a moderately conserved amino acid residue located in a domain of the RAC1 protein that is known to be functional. The p.Val51Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL). -

Sep 17, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31785789, 35139179, 37059841, 37204479, 28886345, 35982159, 28135719, 33057194, 30696065, 34943902, 35851598) -

Intellectual disability, autosomal dominant 48 Pathogenic:1

Mar 28, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.18	B;.
Vest4		0.65
MutPred		0.52		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.95
MPC		3.4
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.95
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554263625; hg19: chr7-6431598;