2-38962849-CAAAAAAAAAAA-CAAAAAAAAAA

Variant names:

• chr2-38962849-CA-C
• rs386389985
• NM_001145451.5:c.2343+2226delA

Variant summary

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

The NM_001145451.5(ARHGEF33):​c.2343+2226delA 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 0.00025 (0 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: 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+2226delA		intron_variant	Intron 16 of 17	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3	c.2343+2226delA		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+2202delA		intron_variant	Intron 16 of 17	5	NM_001145451.5	ENSP00000387020.1

Frequencies

GnomAD3 genomes AF: 0.000249 AC: 14 AN: 56132 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000937

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00181

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000871

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000249 AC: 14 AN: 56124 Hom.: 0 Cov.: 0 AF XY: 0.000370 AC XY: 9 AN XY: 24330

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

African (AFR) AF: 0.000413 AC: 5 AN: 12110

American (AMR) AF: 0.000938 AC: 3 AN: 3198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1960

East Asian (EAS) AF: 0.00183 AC: 3 AN: 1642

South Asian (SAS) AF: 0.00 AC: 0 AN: 1172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 414

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

European-Non Finnish (NFE) AF: 0.0000871 AC: 3 AN: 34452

Other (OTH) AF: 0.00 AC: 0 AN: 646

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000836), which strongly suggests a high chance of mosaicism in these individuals.

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

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: rs386389985; hg19: chr2-39189990;