2-38962849-C-CAAAA

Variant names:

• chr2-38962849-C-CAAAA
• rs386389985
• NM_001145451.5:c.2343+2223_2343+2226dupAAAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001145451.5(ARHGEF33):​c.2343+2223_2343+2226dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.0027 (3 hom., cov: 0)
• Consequence: ARHGEF33 NM_001145451.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-38962849-C-CAAAA is Benign according to our data. Variant chr2-38962849-C-CAAAA is described in ClinVar as [Benign]. Clinvar id is 3389483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5	c.2343+2223_2343+2226dupAAAA		intron_variant	Intron 16 of 17	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3	c.2343+2223_2343+2226dupAAAA		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+2202insAAAA		intron_variant	Intron 16 of 17	5	NM_001145451.5	ENSP00000387020.1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 153 AN: 55752 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.00612

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00205

Gnomad EAS AF: 0.00242

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00971

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00310

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

GnomAD4 genome AF: 0.00274 AC: 153 AN: 55744 Hom.: 3 Cov.: 0 AF XY: 0.00265 AC XY: 64 AN XY: 24166

African (AFR) AF: 0.00515 AC: 61 AN: 11846

American (AMR) AF: 0.00313 AC: 10 AN: 3190

Ashkenazi Jewish (ASJ) AF: 0.00205 AC: 4 AN: 1954

East Asian (EAS) AF: 0.00244 AC: 4 AN: 1636

South Asian (SAS) AF: 0.00 AC: 0 AN: 1170

European-Finnish (FIN) AF: 0.00971 AC: 4 AN: 412

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

European-Non Finnish (NFE) AF: 0.00189 AC: 65 AN: 34360

Other (OTH) AF: 0.00310 AC: 2 AN: 646

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOS1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

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;