chr12-57616380-A-C

Position:

• chr12-57616380-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182947.4(ARHGEF25):​c.1517A>C​(p.Gln506Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q506R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06312993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF25	NM_182947.4	c.1517A>C	p.Gln506Pro	missense_variant	14/15	ENST00000286494.9	NP_891992.3
ARHGEF25	NM_001111270.3	c.1634A>C	p.Gln545Pro	missense_variant	15/16		NP_001104740.2
ARHGEF25	NM_001347933.2	c.1427A>C	p.Gln476Pro	missense_variant	13/14		NP_001334862.2
ARHGEF25	NR_046223.2	n.2007A>C		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>C	p.Gln506Pro	missense_variant	14/15	1	NM_182947.4	ENSP00000286494.4
ENSG00000287908	ENST00000474359.7	n.512A>C		non_coding_transcript_exon_variant	4/23	5		ENSP00000431994.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 65 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.65
DEOGEN2	Benign	0.0090	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.9	N;N;.
REVEL	Benign	0.052
Sift	Benign	0.060	T;T;.
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0050	.;B;.
Vest4		0.13
MutPred		0.18		.;Gain of methylation at R504 (P = 0.0573);.;
MVP		0.13
MPC		0.27
ClinPred		0.047	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.31

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;