2-38962849-CAAAAAAAAAAA-CAAAAAAAAAAAAAA

Variant names:

• chr2-38962849-C-CAAA
• rs386389985
• NM_001145451.5:c.2343+2224_2343+2226dupAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001145451.5(ARHGEF33):​c.2343+2224_2343+2226dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.054 (304 hom., cov: 0)
• Consequence: ARHGEF33 NM_001145451.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 1 publications found

Genes affected

ARHGEF33 (HGNC:37252): (Rho guanine nucleotide exchange factor 33) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

SOS1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• fibromatosis, gingival, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary gingival fibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5	c.2343+2224_2343+2226dupAAA		intron_variant	Intron 16 of 17	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3	c.2343+2224_2343+2226dupAAA		intron_variant	Intron 16 of 18		NP_001354552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.2343+2201_2343+2202insAAA		intron_variant	Intron 16 of 17	5	NM_001145451.5	ENSP00000387020.1

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 3005 AN: 55886 Hom.: 304 Cov.: 0

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.0539

Gnomad SAS AF: 0.0349

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0588

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0538 AC: 3007 AN: 55878 Hom.: 304 Cov.: 0 AF XY: 0.0568 AC XY: 1376 AN XY: 24234

African (AFR) AF: 0.0902 AC: 1088 AN: 12068

American (AMR) AF: 0.0492 AC: 157 AN: 3190

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 118 AN: 1950

East Asian (EAS) AF: 0.0538 AC: 88 AN: 1636

South Asian (SAS) AF: 0.0352 AC: 41 AN: 1164

European-Finnish (FIN) AF: 0.0411 AC: 17 AN: 414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 40

European-Non Finnish (NFE) AF: 0.0410 AC: 1404 AN: 34280

Other (OTH) AF: 0.0588 AC: 38 AN: 646

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386389985; hg19: chr2-39189990;