chr14-21074403-C-T

Variant names:

• chr14-21074403-C-T
• NM_018071.5:c.673C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278529.2(ARHGEF40):​c.-1497C>T variant causes a 5 prime UTR premature start codon gain 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF40 NM_001278529.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.827
• Publications: 0 publications found

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

ACMG classification

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_001278529.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	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

Sel.	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.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ARHGEF40 related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.83
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.28	B
Vest4		0.62
MutPred		0.21		Loss of catalytic residue at R225 (P = 0.0402)
MVP		0.24
MPC		0.88
ClinPred		0.65	D
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

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

Other links and lift over

hg19: chr14-21542562; COSMIC: COSV100070659; COSMIC: COSV100070659;