4-105613429-G-C

Variant names:

• chr4-105613429-G-C
• NM_001242729.2:c.430G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001242729.2(ARHGEF38):​c.430G>C​(p.Val144Leu) variant causes a missense change. 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. V144M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF38 NM_001242729.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

Genes affected

ARHGEF38 (HGNC:25968): (Rho guanine nucleotide exchange factor 38) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF38 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38648826).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242729.2. 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
	ARHGEF38	NM_001242729.2	MANE Select	c.430G>C	p.Val144Leu	missense	Exon 3 of 14	NP_001229658.1	Q9NXL2-2
	ARHGEF38	NM_017700.2		c.430G>C	p.Val144Leu	missense	Exon 3 of 4	NP_060170.1	Q9NXL2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF38	ENST00000420470.3	TSL:5 MANE Select	c.430G>C	p.Val144Leu	missense	Exon 3 of 14	ENSP00000416125.2	Q9NXL2-2
	ARHGEF38	ENST00000265154.6	TSL:1	c.430G>C	p.Val144Leu	missense	Exon 3 of 4	ENSP00000265154.2	Q9NXL2-1
	ARHGEF38	ENST00000506828.1	TSL:5	n.303G>C		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Benign	0.031	D
Sift4G	Benign	0.11	T
Polyphen		0.25	B
Vest4		0.56
MutPred		0.62		Gain of catalytic residue at V144 (P = 0.0329)
MVP		0.13
MPC		0.070
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.47
Mutation Taster		=72/28	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: chr4-106534586;