4-105613493-C-T

Variant names:

• chr4-105613493-C-T
• rs1728387669
• NM_001242729.2:c.494C>T

Variant summary

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

The NM_001242729.2(ARHGEF38):​c.494C>T​(p.Ala165Val) 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. 16/22 in silico tools predict 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. A165T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF38 NM_001242729.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• 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=0.30070707).

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.494C>T	p.Ala165Val	missense	Exon 3 of 14	NP_001229658.1	Q9NXL2-2
	ARHGEF38	NM_017700.2		c.494C>T	p.Ala165Val	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.494C>T	p.Ala165Val	missense	Exon 3 of 14	ENSP00000416125.2	Q9NXL2-2
	ARHGEF38	ENST00000265154.6	TSL:1	c.494C>T	p.Ala165Val	missense	Exon 3 of 4	ENSP00000265154.2	Q9NXL2-1
	ARHGEF38	ENST00000506828.1	TSL:5	n.367C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.094
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0016	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.63	N
PhyloP100		1.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.89	P
Vest4		0.42
MutPred		0.44		Loss of disorder (P = 0.0796)
MVP		0.47
MPC		0.19
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.16
gMVP		0.17
Mutation Taster		=89/11	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

dbSNP: rs1728387669; hg19: chr4-106534650; COSMIC: COSV54442089;