12-57616380-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182947.4(ARHGEF25):​c.1517A>T​(p.Gln506Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 32)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070029646).

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>T	p.Gln506Leu	missense	Exon 14 of 15	NP_891992.3
	ARHGEF25	NM_001111270.3		c.1634A>T	p.Gln545Leu	missense	Exon 15 of 16	NP_001104740.2
	ARHGEF25	NM_001347933.2		c.1427A>T	p.Gln476Leu	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>T	p.Gln506Leu	missense	Exon 14 of 15	ENSP00000286494.4
	ARHGEF25	ENST00000333972.11	TSL:1	c.1634A>T	p.Gln545Leu	missense	Exon 15 of 16	ENSP00000335560.7
	ENSG00000287908	ENST00000474359.7	TSL:5	n.512A>T		non_coding_transcript_exon	Exon 4 of 23	ENSP00000431994.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.36
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.026
Sift	Benign	0.070	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.22		Gain of methylation at R504 (P = 0.1048)
MVP		0.14
MPC		0.23
ClinPred		0.045	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.31
Mutation Taster		=87/13	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

dbSNP: rs1564374; hg19: chr12-58010163;