chr7-6401627-G-C

Variant names:

• chr7-6401627-G-C
• rs6954996
• NM_006908.5:c.289-241G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006908.5(RAC1):​c.289-241G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 170,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RAC1 NM_006908.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5	c.289-241G>C		intron_variant	Intron 4 of 5	ENST00000348035.9	NP_008839.2
RAC1	NM_018890.4	c.346-241G>C		intron_variant	Intron 5 of 6		NP_061485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9	c.289-241G>C		intron_variant	Intron 4 of 5	1	NM_006908.5	ENSP00000258737.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000176 AC: 3 AN: 170018 Hom.: 0 Cov.: 3 AF XY: 0.0000348 AC XY: 3 AN XY: 86250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 5230

American (AMR) AF: 0.00 AC: 0 AN: 5358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6532

East Asian (EAS) AF: 0.00 AC: 0 AN: 14156

South Asian (SAS) AF: 0.000441 AC: 3 AN: 6802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 107264

Other (OTH) AF: 0.00 AC: 0 AN: 11402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.024570), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.25
DANN	Benign	0.47
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6954996; hg19: chr7-6441258;