rs114537415

Variant names:

• chr11-120429739-C-T
• rs114537415
• NM_015313.3:c.691C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015313.3(ARHGEF12):​c.691C>T​(p.Pro231Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000721 in 1,613,640 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: ARHGEF12 NM_015313.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.78
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004073918).
• BP6: Variant 11-120429739-C-T is Benign according to our data. Variant chr11-120429739-C-T is described in ClinVar as Benign. ClinVar VariationId is 787914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 618 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.691C>T	p.Pro231Ser	missense	Exon 10 of 41	NP_056128.1	Q9NZN5-1
	ARHGEF12	NM_001198665.2		c.634C>T	p.Pro212Ser	missense	Exon 9 of 40	NP_001185594.1	Q9NZN5-2
	ARHGEF12	NM_001301084.2		c.382C>T	p.Pro128Ser	missense	Exon 10 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.691C>T	p.Pro231Ser	missense	Exon 10 of 41	ENSP00000380942.2	Q9NZN5-1
	ARHGEF12	ENST00000532993.5	TSL:1	c.382C>T	p.Pro128Ser	missense	Exon 10 of 41	ENSP00000432984.1	E9PMR6
	ARHGEF12	ENST00000356641.7	TSL:5	c.634C>T	p.Pro212Ser	missense	Exon 9 of 40	ENSP00000349056.3	Q9NZN5-2

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 617 AN: 152132 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00100 AC: 250 AN: 248778 AF XY: 0.000808

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000374 AC: 546 AN: 1461390 Hom.: 4 Cov.: 31 AF XY: 0.000282 AC XY: 205 AN XY: 726944

African (AFR) AF: 0.0136 AC: 455 AN: 33464

American (AMR) AF: 0.000783 AC: 35 AN: 44690

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111792

Other (OTH) AF: 0.000812 AC: 49 AN: 60378

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152250 Hom.: 7 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74448

African (AFR) AF: 0.0134 AC: 558 AN: 41542

American (AMR) AF: 0.00307 AC: 47 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00159 Hom.: 2

Bravo AF: 0.00494

ESP6500AA AF: 0.0103 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00133 AC: 160

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.054
Sift	Benign	0.093	T
Sift4G	Benign	0.073	T
Polyphen		0.10	B
Vest4		0.21
MVP		0.45
MPC		0.56
ClinPred		0.075	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.18
gMVP		0.43
Mutation Taster		=86/14	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: rs114537415; hg19: chr11-120300448;