14-21074907-C-G

Position:

• chr14-21074907-C-G

Variant summary

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

The NM_018071.5(ARHGEF40):​c.1177C>G​(p.Arg393Gly) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF40 NM_018071.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.188

Genes affected

ARHGEF40 (HGNC:25516): (Rho guanine nucleotide exchange factor 40) This gene encodes a protein similar to guanosine nucleotide exchange factors for Rho GTPases. The encoded protein contains in its C-terminus a GEF domain involved in exchange activity and a pleckstrin homology domain. Alternatively spliced transcripts that encode different proteins have been described. [provided by RefSeq, Mar 2014]

ARHGEF40 (HGNC:):

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=0.17643324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF40	NM_018071.5	c.1177C>G	p.Arg393Gly	missense_variant	3/24	ENST00000298694.9	NP_060541.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF40	ENST00000298694.9	c.1177C>G	p.Arg393Gly	missense_variant	3/24	2	NM_018071.5	ENSP00000298694.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

research

Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, University of Tampere

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	0.050
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.89	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.088
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.88	P;D
Vest4		0.34
MutPred		0.35		Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);
MVP		0.36
MPC		0.35
ClinPred		0.69	D
GERP RS		4.2
Varity_R		0.14
gMVP		0.48

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: rs753872972; hg19: chr14-21543066; COSMIC: COSV53879463; COSMIC: COSV53879463;