7-6374747-C-G

Variant names:

• chr7-6374747-C-G
• rs1322357597
• NM_006908.5:c.12C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_006908.5(RAC1):​c.12C>G​(p.Ile4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAC1 NM_006908.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.812
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a chain Ras-related C3 botulinum toxin substrate 1 (size 188) in uniprot entity RAC1_HUMAN there are 25 pathogenic changes around while only 1 benign (96%) in NM_006908.5
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37519878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5	c.12C>G	p.Ile4Met	missense_variant	Exon 1 of 6	ENST00000348035.9	NP_008839.2
RAC1	NM_018890.4	c.12C>G	p.Ile4Met	missense_variant	Exon 1 of 7		NP_061485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9	c.12C>G	p.Ile4Met	missense_variant	Exon 1 of 6	1	NM_006908.5	ENSP00000258737.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1000260 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 480736

African (AFR) AF: 0.00 AC: 0 AN: 19110

American (AMR) AF: 0.00 AC: 0 AN: 7538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10702

East Asian (EAS) AF: 0.00 AC: 0 AN: 14764

South Asian (SAS) AF: 0.00 AC: 0 AN: 27064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 860174

Other (OTH) AF: 0.00 AC: 0 AN: 35908

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAC1 c.12C>G (p.Ile4Met) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 32958 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.12C>G in individuals affected with Intellectual Disability, Autosomal Dominant 48 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		0.81
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.018	B;.
Vest4		0.39
MutPred		0.74		Gain of disorder (P = 0.0182);Gain of disorder (P = 0.0182);
MVP		0.79
MPC		2.5
ClinPred		0.87	D
GERP RS		3.2
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.81
gMVP		0.88
Mutation Taster		=60/40	polymorphism

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: rs1322357597; hg19: chr7-6414378;