Variant 11-120431816-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015313.3(ARHGEF12):c.829A>G(p.Thr277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ARHGEF12
NM_015313.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.117

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05053118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF12	NM_015313.3 linkuse as main transcript	c.829A>G	p.Thr277Ala	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.829A>G	p.Thr277Ala	missense_variant	11/41	1	NM_015313.3	ENSP00000380942.2	Q9NZN5-1
ARHGEF12	ENST00000532993.5 linkuse as main transcript	c.520A>G	p.Thr174Ala	missense_variant	11/41	1		ENSP00000432984.1	E9PMR6
ARHGEF12	ENST00000356641.7 linkuse as main transcript	c.772A>G	p.Thr258Ala	missense_variant	10/40	5		ENSP00000349056.3	Q9NZN5-2
ARHGEF12	ENST00000529970.5 linkuse as main transcript	n.963A>G		non_coding_transcript_exon_variant	11/36	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Aug 28, 2024

The c.829A>G (p.T277A) alteration is located in exon 11 (coding exon 11) of the ARHGEF12 gene. This alteration results from a A to G substitution at nucleotide position 829, causing the threonine (T) at amino acid position 277 to be replaced by an alanine (A). 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

0.061

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.2

DANN

Benign

0.90

DEOGEN2

Benign

0.042

.;T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.27

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.030

MutPred

0.19

.;Loss of phosphorylation at T277 (P = 0.0315);.;

MVP

0.40

MPC

0.52

ClinPred

0.034

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.030

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

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