Variant 11-120431888-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015313.3(ARHGEF12):c.901C>T(p.Arg301Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,458,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

ARHGEF12
NM_015313.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.833

Variant links:

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 links:

ARHGEF12 (HGNC:):

ARHGEF12 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.113509476).

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF12	NM_015313.3 linkuse as main transcript	c.901C>T	p.Arg301Trp	missense_variant	11/41	ENST00000397843.7	NP_056128.1	Q9NZN5-1B4E2K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARHGEF12	ENST00000397843.7 linkuse as main transcript	c.901C>T	p.Arg301Trp	missense_variant	11/41	1	NM_015313.3	ENSP00000380942.2	Q9NZN5-1
ARHGEF12	ENST00000532993.5 linkuse as main transcript	c.592C>T	p.Arg198Trp	missense_variant	11/41	1		ENSP00000432984.1	E9PMR6
ARHGEF12	ENST00000356641.7 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	10/40	5		ENSP00000349056.3	Q9NZN5-2
ARHGEF12	ENST00000529970.5 linkuse as main transcript	n.1035C>T		non_coding_transcript_exon_variant	11/36	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000572

AC:

AN:

244670

Hom.:

AF XY:

0.0000754

AC XY:

AN XY:

132680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000479

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1458034

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

725176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000470

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.901C>T (p.R301W) alteration is located in exon 11 (coding exon 11) of the ARHGEF12 gene. This alteration results from a C to T substitution at nucleotide position 901, causing the arginine (R) at amino acid position 301 to be replaced by a tryptophan (W). 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

0.059

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

.;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.031

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.021

D;D;D

Sift4G

Benign

0.19

T;T;T

Polyphen

0.061

B;B;.

Vest4

0.20

MutPred

0.23

.;Gain of catalytic residue at R301 (P = 0.0394);.;

MVP

0.60

MPC

0.56

ClinPred

0.17

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over