chr11-120431787-C-T

Variant names:

• chr11-120431787-C-T
• rs781232750
• NM_015313.3:c.800C>T

Variant summary

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

The NM_015313.3(ARHGEF12):​c.800C>T​(p.Thr267Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,455,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: 0.000014 (0 hom.)
• Consequence: ARHGEF12 NM_015313.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190
• Publications: 0 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=0.05738938).
• BS2: High AC in GnomAdExome4 at 20 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.800C>T	p.Thr267Ile	missense	Exon 11 of 41	NP_056128.1	Q9NZN5-1
	ARHGEF12	NM_001198665.2		c.743C>T	p.Thr248Ile	missense	Exon 10 of 40	NP_001185594.1	Q9NZN5-2
	ARHGEF12	NM_001301084.2		c.491C>T	p.Thr164Ile	missense	Exon 11 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.800C>T	p.Thr267Ile	missense	Exon 11 of 41	ENSP00000380942.2	Q9NZN5-1
	ARHGEF12	ENST00000532993.5	TSL:1	c.491C>T	p.Thr164Ile	missense	Exon 11 of 41	ENSP00000432984.1	E9PMR6
	ARHGEF12	ENST00000356641.7	TSL:5	c.743C>T	p.Thr248Ile	missense	Exon 10 of 40	ENSP00000349056.3	Q9NZN5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 244456 AF XY: 0.0000151

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1455244 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 723762

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.00 AC: 0 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000708 AC: 6 AN: 84796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1109548

Other (OTH) AF: 0.00 AC: 0 AN: 60080

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.19
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.014
Sift	Benign	0.099	T
Sift4G	Benign	0.47	T
Polyphen		0.054	B
Vest4		0.043
MutPred		0.27		Loss of phosphorylation at T267 (P = 0.0071)
MVP		0.35
MPC		0.58
ClinPred		0.026	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.021
gMVP		0.18
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs781232750; hg19: chr11-120302496;