12-57616380-A-G

Variant names:

• chr12-57616380-A-G
• rs1564374
• NM_182947.4:c.1517A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182947.4(ARHGEF25):​c.1517A>G​(p.Gln506Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,794 control chromosomes in the GnomAD database, including 289,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (25988 hom., cov: 32)
  • Exomes 𝑓: 0.60 (263067 hom.)
• Consequence: ARHGEF25 NM_182947.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.364
• Publications: 44 publications found

Genes affected

ARHGEF25 (HGNC:30275): (Rho guanine nucleotide exchange factor 25) Rho GTPases alternate between an inactive GDP-bound state and an active GTP-bound state, and GEFs facilitate GDP/GTP exchange. This gene encodes a guanine nucleotide exchange factor (GEF) which interacts with Rho GTPases involved in contraction of vascular smooth muscles, regulation of responses to angiotensin II and lens cell differentiation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ENSG00000287908 (HGNC:):

ENSG00000224713 (HGNC:41260):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9157078E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182947.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF25	NM_182947.4	MANE Select	c.1517A>G	p.Gln506Arg	missense	Exon 14 of 15	NP_891992.3
	ARHGEF25	NM_001111270.3		c.1634A>G	p.Gln545Arg	missense	Exon 15 of 16	NP_001104740.2
	ARHGEF25	NM_001347933.2		c.1427A>G	p.Gln476Arg	missense	Exon 13 of 14	NP_001334862.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF25	ENST00000286494.9	TSL:1 MANE Select	c.1517A>G	p.Gln506Arg	missense	Exon 14 of 15	ENSP00000286494.4
	ARHGEF25	ENST00000333972.11	TSL:1	c.1634A>G	p.Gln545Arg	missense	Exon 15 of 16	ENSP00000335560.7
	ENSG00000287908	ENST00000474359.7	TSL:5	n.512A>G		non_coding_transcript_exon	Exon 4 of 23	ENSP00000431994.2

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88125 AN: 151878 Hom.: 25956 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.527

GnomAD2 exomes AF: 0.626 AC: 157293 AN: 251212 AF XY: 0.624

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.768

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.575

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.596 AC: 870827 AN: 1461798 Hom.: 263067 Cov.: 65 AF XY: 0.598 AC XY: 434667 AN XY: 727204

African (AFR) AF: 0.543 AC: 18178 AN: 33480

American (AMR) AF: 0.712 AC: 31859 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11703 AN: 26130

East Asian (EAS) AF: 0.810 AC: 32159 AN: 39696

South Asian (SAS) AF: 0.714 AC: 61594 AN: 86256

European-Finnish (FIN) AF: 0.639 AC: 34149 AN: 53400

Middle Eastern (MID) AF: 0.434 AC: 2500 AN: 5764

European-Non Finnish (NFE) AF: 0.579 AC: 643671 AN: 1111960

Other (OTH) AF: 0.580 AC: 35014 AN: 60394

GnomAD4 genome AF: 0.580 AC: 88202 AN: 151996 Hom.: 25988 Cov.: 32 AF XY: 0.586 AC XY: 43534 AN XY: 74286

African (AFR) AF: 0.542 AC: 22428 AN: 41414

American (AMR) AF: 0.619 AC: 9457 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3470

East Asian (EAS) AF: 0.764 AC: 3943 AN: 5160

South Asian (SAS) AF: 0.725 AC: 3491 AN: 4814

European-Finnish (FIN) AF: 0.644 AC: 6808 AN: 10568

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38666 AN: 67972

Other (OTH) AF: 0.532 AC: 1124 AN: 2112

Alfa AF: 0.574 Hom.: 80849

Bravo AF: 0.578

TwinsUK AF: 0.571 AC: 2118

ALSPAC AF: 0.576 AC: 2218

ESP6500AA AF: 0.534 AC: 2353

ESP6500EA AF: 0.564 AC: 4851

ExAC AF: 0.625 AC: 75862

Asia WGS AF: 0.723 AC: 2513 AN: 3478

EpiCase AF: 0.542

EpiControl AF: 0.539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.68
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.97	N
PhyloP100		0.36
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.24
ClinPred		0.0017	T
GERP RS		3.7
Varity_R		0.040
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs1564374; hg19: chr12-58010163; COSMIC: COSV54089384; COSMIC: COSV54089384;