2-38950995-C-G

Position:

• chr2-38950995-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145451.5(ARHGEF33):​c.927C>G​(p.Phe309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF33 NM_001145451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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]

LOC105374471 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5	c.927C>G	p.Phe309Leu	missense_variant	11/18	ENST00000409978.7	NP_001138923.2
LOC105374471	XR_939980.3	n.110+1315G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF33	ENST00000409978.7	c.927C>G	p.Phe309Leu	missense_variant	11/18	5	NM_001145451.5	ENSP00000387020	P1
ARHGEF33	ENST00000698009.1	c.1071C>G	p.Phe357Leu	missense_variant	12/19			ENSP00000513494
ARHGEF33	ENST00000398800.8	c.927C>G	p.Phe309Leu	missense_variant	9/16	5		ENSP00000381780	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.927C>G (p.F309L) alteration is located in exon 9 (coding exon 9) of the ARHGEF33 gene. This alteration results from a C to G substitution at nucleotide position 927, causing the phenylalanine (F) at amino acid position 309 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.030
Eigen_PC	Benign	0.0045
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.029	D;D
Sift4G	Uncertain	0.031	D;D
Vest4		0.62
MutPred		0.72		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.45
ClinPred		0.98	D
GERP RS		1.9
gMVP		0.33

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-39178136;