11-120431852-C-G

Position:

• chr11-120431852-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015313.3(ARHGEF12):​c.865C>G​(p.Leu289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF12 NM_015313.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.796

Genes affected

ARHGEF12 (HGNC:14193): (Rho guanine nucleotide exchange factor 12) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli working through G protein-coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. This protein has been observed to form a myeloid/lymphoid fusion partner in acute myeloid leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ARHGEF12 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086357296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF12	NM_015313.3	c.865C>G	p.Leu289Val	missense_variant	11/41	ENST00000397843.7	NP_056128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF12	ENST00000397843.7	c.865C>G	p.Leu289Val	missense_variant	11/41	1	NM_015313.3	ENSP00000380942.2
ARHGEF12	ENST00000532993.5	c.556C>G	p.Leu186Val	missense_variant	11/41	1		ENSP00000432984.1
ARHGEF12	ENST00000356641.7	c.808C>G	p.Leu270Val	missense_variant	10/40	5		ENSP00000349056.3
ARHGEF12	ENST00000529970.5	n.999C>G		non_coding_transcript_exon_variant	11/36	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 27, 2022

The c.865C>G (p.L289V) alteration is located in exon 11 (coding exon 11) of the ARHGEF12 gene. This alteration results from a C to G substitution at nucleotide position 865, causing the leucine (L) at amino acid position 289 to be replaced by a valine (V). 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.094	.;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.069	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.059
MutPred		0.25		.;Loss of catalytic residue at L289 (P = 0.0756);.;
MVP		0.52
MPC		0.54
ClinPred		0.052	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.11

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: chr11-120302561;