14-21081734-GTG-CTT

Variant names:

• chr14-21081734-GTG-CTT
• NM_018071.5:c.2866_2868delGTGinsCTT
• ARHGEF40 p.Val956Leu

Variant summary

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

The NM_018071.5(ARHGEF40):​c.2866_2868delGTGinsCTT​(p.Val956Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ARHGEF40 NM_018071.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF40	NM_018071.5	MANE Select	c.2866_2868delGTGinsCTT	p.Val956Leu	missense	N/A	NP_060541.3
	ARHGEF40	NM_001278529.2		c.724_726delGTGinsCTT	p.Val242Leu	missense	N/A	NP_001265458.1	Q8TER5-2
	ARHGEF40	NM_001278530.2		c.724_726delGTGinsCTT	p.Val242Leu	missense	N/A	NP_001265459.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF40	ENST00000298694.9	TSL:2 MANE Select	c.2866_2868delGTGinsCTT	p.Val956Leu	missense	N/A	ENSP00000298694.4	Q8TER5-1
	ARHGEF40	ENST00000553709.5	TSL:1	n.*1030_*1032delGTGinsCTT		non_coding_transcript_exon	Exon 14 of 24	ENSP00000452283.1	G3V5C1
	ARHGEF40	ENST00000554514.1	TSL:1	n.346_348delGTGinsCTT		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-21549893;