2-38962849-CAAAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

• chr2-38962849-C-CAA
• rs386389985
• NM_001145451.5:c.2343+2225_2343+2226dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001145451.5(ARHGEF33):​c.2343+2225_2343+2226dupAA 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 0.76 (17093 hom., cov: 0)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5	c.2343+2225_2343+2226dupAA		intron_variant	Intron 16 of 17	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3	c.2343+2225_2343+2226dupAA		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+2202insAA		intron_variant	Intron 16 of 17	5	NM_001145451.5	ENSP00000387020.1

Frequencies

GnomAD3 genomes AF: 0.761 AC: 42806 AN: 56278 Hom.: 17100 Cov.: 0

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.839

Gnomad MID AF: 0.833

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.769

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

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.760 AC: 42790 AN: 56270 Hom.: 17093 Cov.: 0 AF XY: 0.750 AC XY: 18322 AN XY: 24416

African (AFR) AF: 0.510 AC: 6188 AN: 12124

American (AMR) AF: 0.805 AC: 2586 AN: 3212

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 1539 AN: 1964

East Asian (EAS) AF: 0.668 AC: 1099 AN: 1644

South Asian (SAS) AF: 0.758 AC: 896 AN: 1182

European-Finnish (FIN) AF: 0.839 AC: 349 AN: 416

Middle Eastern (MID) AF: 0.850 AC: 34 AN: 40

European-Non Finnish (NFE) AF: 0.847 AC: 29261 AN: 34552

Other (OTH) AF: 0.769 AC: 498 AN: 648

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;