4-105552779-A-G

Position:

• chr4-105552779-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242729.2(ARHGEF38):​c.14A>G​(p.Glu5Gly) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 3.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15489063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF38	NM_001242729.2	c.14A>G	p.Glu5Gly	missense_variant	1/14	ENST00000420470.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF38	ENST00000420470.3	c.14A>G	p.Glu5Gly	missense_variant	1/14	5	NM_001242729.2	P1
ARHGEF38	ENST00000265154.6	c.14A>G	p.Glu5Gly	missense_variant	1/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The c.14A>G (p.E5G) alteration is located in exon 1 (coding exon 1) of the ARHGEF38 gene. This alteration results from a A to G substitution at nucleotide position 14, causing the glutamic acid (E) at amino acid position 5 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0068	.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.63	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.0050	.;B
Vest4		0.10
MutPred		0.17		Gain of glycosylation at T7 (P = 0.0304);Gain of glycosylation at T7 (P = 0.0304);
MVP		0.47
MPC		0.048
ClinPred		0.70	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-106473936;