NM_182947.4:c.406C>T

Variant names:

• chr12-57613357-C-T
• rs577533598
• NM_182947.4:c.406C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182947.4(ARHGEF25):​c.406C>T​(p.Gln136*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q136Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF25 NM_182947.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9921
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332
• Publications: 3 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]

ENSG00000224713 (HGNC:41260):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF25	NM_182947.4	MANE Select	c.406C>T	p.Gln136*	stop_gained splice_region	Exon 3 of 15	NP_891992.3	Q86VW2-1
	ARHGEF25	NM_001111270.3		c.523C>T	p.Gln175*	stop_gained splice_region	Exon 4 of 16	NP_001104740.2	Q86VW2-3
	ARHGEF25	NM_001347933.2		c.406C>T	p.Gln136*	stop_gained splice_region	Exon 3 of 14	NP_001334862.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF25	ENST00000286494.9	TSL:1 MANE Select	c.406C>T	p.Gln136*	stop_gained splice_region	Exon 3 of 15	ENSP00000286494.4	Q86VW2-1
	ARHGEF25	ENST00000333972.11	TSL:1	c.523C>T	p.Gln175*	stop_gained splice_region	Exon 4 of 16	ENSP00000335560.7	Q86VW2-3
	ENSG00000224713	ENST00000444467.2	TSL:1	n.1191G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.45	N
PhyloP100		0.33
Vest4		0.21
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=13/187	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs577533598; hg19: chr12-58007140; COSMIC: COSV54087958; COSMIC: COSV54087958;