3-154122194-G-A

Position:

• chr3-154122194-G-A

Variant summary

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

The ENST00000465093.6(ARHGEF26):​c.202G>A​(p.Val68Met) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF26 ENST00000465093.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

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=0.07736546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF26	NM_015595.4	c.202G>A	p.Val68Met	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.202G>A	p.Val68Met	missense_variant	2/15	1	NM_015595.4	ENSP00000423418	P1
ARHGEF26	ENST00000465817.1	c.202G>A	p.Val68Met	missense_variant	2/5	1		ENSP00000423295
ARHGEF26	ENST00000356448.8	c.202G>A	p.Val68Met	missense_variant	2/15	2		ENSP00000348828	P1
ARHGEF26	ENST00000496710.5	c.202G>A	p.Val68Met	missense_variant	2/15	2		ENSP00000424446

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450200 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 720414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 33

ExAC AF: 0.00000829 AC: 1

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

Jan 26, 2022

The c.202G>A (p.V68M) alteration is located in exon 2 (coding exon 1) of the ARHGEF26 gene. This alteration results from a G to A substitution at nucleotide position 202, causing the valine (V) at amino acid position 68 to be replaced by a methionine (M). 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	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0026	T;T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.077	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.43	N;N;N;N
REVEL	Benign	0.022
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Benign	0.088	T;T;T;T
Polyphen		0.034	B;B;.;.
Vest4		0.15
MutPred		0.22		Gain of glycosylation at P69 (P = 0.0914);Gain of glycosylation at P69 (P = 0.0914);Gain of glycosylation at P69 (P = 0.0914);Gain of glycosylation at P69 (P = 0.0914);
MVP		0.26
MPC		0.12
ClinPred		0.10	T
GERP RS		3.3
Varity_R		0.068
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760291288; hg19: chr3-153839983;