11-120428210-G-T

Variant names:

• chr11-120428210-G-T
• NM_015313.3:c.548G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015313.3(ARHGEF12):​c.548G>T​(p.Gly183Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,324 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGEF12 NM_015313.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3647314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF12	NM_015313.3	c.548G>T	p.Gly183Val	missense_variant	Exon 8 of 41	ENST00000397843.7	NP_056128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF12	ENST00000397843.7	c.548G>T	p.Gly183Val	missense_variant	Exon 8 of 41	1	NM_015313.3	ENSP00000380942.2
ARHGEF12	ENST00000532993.5	c.239G>T	p.Gly80Val	missense_variant	Exon 8 of 41	1		ENSP00000432984.1
ARHGEF12	ENST00000356641.7	c.491G>T	p.Gly164Val	missense_variant	Exon 7 of 40	5		ENSP00000349056.3
ARHGEF12	ENST00000529970.5	n.682G>T		non_coding_transcript_exon_variant	Exon 8 of 36	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458324 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.548G>T (p.G183V) alteration is located in exon 8 (coding exon 8) of the ARHGEF12 gene. This alteration results from a G to T substitution at nucleotide position 548, causing the glycine (G) at amino acid position 183 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	0.11
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.15	T;T;T
Polyphen		0.93	P;D;.
Vest4		0.41
MutPred		0.11		.;Loss of glycosylation at S182 (P = 0.022);.;
MVP		0.78
MPC		1.4
ClinPred		0.90	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
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: chr11-120298919;