11-120428158-A-G

Variant names:

• chr11-120428158-A-G
• rs376159779
• NM_015313.3:c.496A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015313.3(ARHGEF12):​c.496A>G​(p.Ile166Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,611,750 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ARHGEF12 NM_015313.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0790
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040306658).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015313.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF12	NM_015313.3	MANE Select	c.496A>G	p.Ile166Val	missense	Exon 8 of 41	NP_056128.1	Q9NZN5-1
	ARHGEF12	NM_001198665.2		c.439A>G	p.Ile147Val	missense	Exon 7 of 40	NP_001185594.1	Q9NZN5-2
	ARHGEF12	NM_001301084.2		c.187A>G	p.Ile63Val	missense	Exon 8 of 41	NP_001288013.1	E9PMR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF12	ENST00000397843.7	TSL:1 MANE Select	c.496A>G	p.Ile166Val	missense	Exon 8 of 41	ENSP00000380942.2	Q9NZN5-1
	ARHGEF12	ENST00000532993.5	TSL:1	c.187A>G	p.Ile63Val	missense	Exon 8 of 41	ENSP00000432984.1	E9PMR6
	ARHGEF12	ENST00000356641.7	TSL:5	c.439A>G	p.Ile147Val	missense	Exon 7 of 40	ENSP00000349056.3	Q9NZN5-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000646 AC: 16 AN: 247594 AF XY: 0.0000968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1459600 Hom.: 1 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 725884

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000677 AC: 3 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1111124

Other (OTH) AF: 0.000116 AC: 7 AN: 60340

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000179

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.9
DANN	Benign	0.84
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.079
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.091
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.066
MVP		0.35
MPC		0.44
ClinPred		0.023	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
gMVP		0.082
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs376159779; hg19: chr11-120298867;