3-154122117-G-C

Position:

• chr3-154122117-G-C

Variant summary

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

The NM_015595.4(ARHGEF26):​c.125G>C​(p.Ser42Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF26 NM_015595.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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=0.24250934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF26	NM_015595.4	c.125G>C	p.Ser42Thr	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.125G>C	p.Ser42Thr	missense_variant	2/15	1	NM_015595.4	ENSP00000423418.1
ARHGEF26	ENST00000465817.1	c.125G>C	p.Ser42Thr	missense_variant	2/5	1		ENSP00000423295.1
ARHGEF26	ENST00000356448.8	c.125G>C	p.Ser42Thr	missense_variant	2/15	2		ENSP00000348828.4
ARHGEF26	ENST00000496710.5	c.125G>C	p.Ser42Thr	missense_variant	2/15	2		ENSP00000424446.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

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 Cov.: 90

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 15, 2023

The c.125G>C (p.S42T) alteration is located in exon 2 (coding exon 1) of the ARHGEF26 gene. This alteration results from a G to C substitution at nucleotide position 125, causing the serine (S) at amino acid position 42 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0029	T;T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	.;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.0	M;M;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.71	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.40
MutPred		0.087		Gain of phosphorylation at S42 (P = 0.0519);Gain of phosphorylation at S42 (P = 0.0519);Gain of phosphorylation at S42 (P = 0.0519);Gain of phosphorylation at S42 (P = 0.0519);
MVP		0.58
MPC		0.22
ClinPred		0.50	D
GERP RS		4.5
Varity_R		0.31
gMVP		0.32

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: rs1385301187; hg19: chr3-153839906;