Genetic Variant NM_018071.5:c.673C>T (chr14-21074403-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018071.5(ARHGEF40):c.673C>T(p.Arg225Trp) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ARHGEF40
NM_018071.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.827

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ARHGEF40 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12925783).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018071.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF40	NM_018071.5	MANE Select	c.673C>T	p.Arg225Trp	missense	Exon 3 of 24	NP_060541.3
ARHGEF40	NM_001278529.2		c.-1497C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 24	NP_001265458.1	Q8TER5-2
ARHGEF40	NM_001278530.2		c.-1303C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 23	NP_001265459.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF40	ENST00000298694.9	TSL:2 MANE Select	c.673C>T	p.Arg225Trp	missense	Exon 3 of 24	ENSP00000298694.4	Q8TER5-1
ARHGEF40	ENST00000555038.5	TSL:1	c.673C>T	p.Arg225Trp	missense	Exon 3 of 4	ENSP00000451335.1	G3V3N2
ARHGEF40	ENST00000553709.5	TSL:1	n.673C>T		non_coding_transcript_exon	Exon 3 of 24	ENSP00000452283.1	G3V5C1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ARHGEF40 related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.030

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

PhyloP100

0.83

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.69

REVEL

Benign

0.13

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.28

Vest4

0.62

MutPred

0.21

Loss of catalytic residue at R225 (P = 0.0402)

MVP

0.24

MPC

0.88

ClinPred

0.65

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.51

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over