chr3-154122437-A-C

Position:

• chr3-154122437-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000465093.6(ARHGEF26):​c.445A>C​(p.Thr149Pro) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF26 ENST00000465093.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.500

Genes affected

ARHGEF26 (HGNC:24490): (Rho guanine nucleotide exchange factor 26) This gene encodes a member of the Rho-guanine nucleotide exchange factor (Rho-GEF) family. These proteins regulate Rho GTPases by catalyzing the exchange of GDP for GTP. The encoded protein specifically activates RhoG and plays a role in the promotion of macropinocytosis. Underexpression of the encoded protein may be a predictive marker of chemoresistant disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08191937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF26	NM_015595.4	c.445A>C	p.Thr149Pro	missense_variant	2/15	ENST00000465093.6	NP_056410.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF26	ENST00000465093.6	c.445A>C	p.Thr149Pro	missense_variant	2/15	1	NM_015595.4	ENSP00000423418	P1
ARHGEF26	ENST00000465817.1	c.445A>C	p.Thr149Pro	missense_variant	2/5	1		ENSP00000423295
ARHGEF26	ENST00000356448.8	c.445A>C	p.Thr149Pro	missense_variant	2/15	2		ENSP00000348828	P1
ARHGEF26	ENST00000496710.5	c.445A>C	p.Thr149Pro	missense_variant	2/15	2		ENSP00000424446

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

The c.445A>C (p.T149P) alteration is located in exon 2 (coding exon 1) of the ARHGEF26 gene. This alteration results from a A to C substitution at nucleotide position 445, causing the threonine (T) at amino acid position 149 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00045	T;T;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.60	.;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M;M
MutationTaster	Benign	0.60	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.78	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.068	T;T;T;D
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.088
MutPred		0.21		Loss of phosphorylation at T149 (P = 0.0016);Loss of phosphorylation at T149 (P = 0.0016);Loss of phosphorylation at T149 (P = 0.0016);Loss of phosphorylation at T149 (P = 0.0016);
MVP		0.35
MPC		0.11
ClinPred		0.15	T
GERP RS		2.2
Varity_R		0.18
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-153840226;