chr12-57616380-A-G

Position:

• chr12-57616380-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF25	NM_182947.4	c.1517A>G	p.Gln506Arg	missense_variant	14/15	ENST00000286494.9	NP_891992.3
ARHGEF25	NM_001111270.3	c.1634A>G	p.Gln545Arg	missense_variant	15/16		NP_001104740.2
ARHGEF25	NM_001347933.2	c.1427A>G	p.Gln476Arg	missense_variant	13/14		NP_001334862.2
ARHGEF25	NR_046223.2	n.2007A>G		non_coding_transcript_exon_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF25	ENST00000286494.9	c.1517A>G	p.Gln506Arg	missense_variant	14/15	1	NM_182947.4	ENSP00000286494.4
ENSG00000287908	ENST00000474359.7	n.512A>G		non_coding_transcript_exon_variant	4/23	5		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

GnomAD3 exomes AF: 0.626 AC: 157293 AN: 251212 Hom.: 50486 AF XY: 0.624 AC XY: 84720 AN XY: 135782

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 SAS exome AF: 0.716

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

Gnomad4 AFR exome AF: 0.543

Gnomad4 AMR exome AF: 0.712

Gnomad4 ASJ exome AF: 0.448

Gnomad4 EAS exome AF: 0.810

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.580

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

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.725

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.569

Gnomad4 OTH AF: 0.532

Alfa AF: 0.568 Hom.: 36786

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 v4.3

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;T;T
MetaRNN	Benign	0.0000019	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.97	.;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.32	N;N;.
REVEL	Benign	0.039
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.58	T;T;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

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

Publications

LitVar

Other links and lift over

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