11-120431886-C-T

Variant names:

• chr11-120431886-C-T
• NM_015313.3:c.899C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015313.3(ARHGEF12):​c.899C>T​(p.Ser300Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGEF12 NM_015313.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.899C>T	p.Ser300Phe	missense	Exon 11 of 41	NP_056128.1	Q9NZN5-1
	ARHGEF12	NM_001198665.2		c.842C>T	p.Ser281Phe	missense	Exon 10 of 40	NP_001185594.1	Q9NZN5-2
	ARHGEF12	NM_001301084.2		c.590C>T	p.Ser197Phe	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.899C>T	p.Ser300Phe	missense	Exon 11 of 41	ENSP00000380942.2	Q9NZN5-1
	ARHGEF12	ENST00000532993.5	TSL:1	c.590C>T	p.Ser197Phe	missense	Exon 11 of 41	ENSP00000432984.1	E9PMR6
	ARHGEF12	ENST00000356641.7	TSL:5	c.842C>T	p.Ser281Phe	missense	Exon 10 of 40	ENSP00000349056.3	Q9NZN5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458400 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725360

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 43912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110888

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

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	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.18
Sift	Benign	0.035	D
Sift4G	Uncertain	0.047	D
Polyphen		0.98	D
Vest4		0.69
MutPred		0.28		Loss of phosphorylation at S300 (P = 0.0032)
MVP		0.76
MPC		0.65
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.16
gMVP		0.22
Mutation Taster		=84/16	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

hg19: chr11-120302595;