Variant chr11-120437308-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_015313.3(ARHGEF12):c.925A>G(p.Ser309Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000685 in 1,606,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ARHGEF12
NM_015313.3 missense, splice_region

Scores

Splicing: ADA: 0.5779

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.01

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity ARHGC_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.23632044).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF12	NM_015313.3 linkuse as main transcript	c.925A>G	p.Ser309Gly	missense_variant, splice_region_variant	12/41	ENST00000397843.7	NP_056128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF12	ENST00000397843.7 linkuse as main transcript	c.925A>G	p.Ser309Gly	missense_variant, splice_region_variant	12/41	1	NM_015313.3	ENSP00000380942	P4	Q9NZN5-1
ARHGEF12	ENST00000532993.5 linkuse as main transcript	c.616A>G	p.Ser206Gly	missense_variant, splice_region_variant	12/41	1		ENSP00000432984
ARHGEF12	ENST00000356641.7 linkuse as main transcript	c.868A>G	p.Ser290Gly	missense_variant, splice_region_variant	11/40	5		ENSP00000349056	A1	Q9NZN5-2
ARHGEF12	ENST00000529970.5 linkuse as main transcript	n.1059A>G		splice_region_variant, non_coding_transcript_exon_variant	12/36	2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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

AF:

0.00000344

AC:

AN:

1454434

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723484

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000328

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

Alfa

AF:

0.0000516

Hom.:

Bravo

AF:

0.0000227

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

May 09, 2022

The c.925A>G (p.S309G) alteration is located in exon 12 (coding exon 12) of the ARHGEF12 gene. This alteration results from a A to G substitution at nucleotide position 925, causing the serine (S) at amino acid position 309 to be replaced by a glycine (G). 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

0.19

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.92

P;P;.

Vest4

0.46

MVP

0.79

MPC

0.50

ClinPred

0.85

GERP RS

5.3

Varity_R

0.18

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.58

dbscSNV1_RF

Benign

0.68

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