NM_001145451.5:c.2343+2156G>A

Variant names:

• chr2-38962804-G-A
• rs186949565
• NM_001145451.5:c.2343+2156G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001145451.5(ARHGEF33):​c.2343+2156G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 129,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0036 (0 hom., cov: 25)
• Consequence: ARHGEF33 NM_001145451.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.458
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• 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
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-38962804-G-A is Benign according to our data. Variant chr2-38962804-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2650843.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145451.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF33	NM_001145451.5	MANE Select	c.2343+2156G>A		intron	N/A	NP_001138923.2	A8MVX0-2
	ARHGEF33	NM_001367623.3		c.2343+2156G>A		intron	N/A	NP_001354552.1	A8MVX0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF33	ENST00000409978.7	TSL:5 MANE Select	c.2343+2156G>A		intron	N/A	ENSP00000387020.1	A8MVX0-2
	SOS1	ENST00000692089.1		c.3441C>T	p.Ser1147Ser	synonymous	Exon 22 of 22	ENSP00000508626.1	A0A8I5QJ77
	ARHGEF33	ENST00000698009.1		c.2487+2156G>A		intron	N/A	ENSP00000513494.1	A0A8V8TLC5

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 469 AN: 129282 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000860

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00530

Gnomad OTH AF: 0.00652

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

GnomAD4 genome AF: 0.00363 AC: 469 AN: 129324 Hom.: 0 Cov.: 25 AF XY: 0.00317 AC XY: 191 AN XY: 60184

African (AFR) AF: 0.00140 AC: 48 AN: 34318

American (AMR) AF: 0.00628 AC: 60 AN: 9560

Ashkenazi Jewish (ASJ) AF: 0.000294 AC: 1 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4444

South Asian (SAS) AF: 0.00 AC: 0 AN: 4184

European-Finnish (FIN) AF: 0.000860 AC: 5 AN: 5814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 140

European-Non Finnish (NFE) AF: 0.00530 AC: 344 AN: 64868

Other (OTH) AF: 0.00648 AC: 11 AN: 1698

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00345

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.86
DANN	Benign	0.85
PhyloP100		0.46

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: rs186949565; hg19: chr2-39189945;