chr4-105589296-C-G

Variant names:

• chr4-105589296-C-G
• NM_001242729.2:c.245C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001242729.2(ARHGEF38):​c.245C>G​(p.Pro82Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ARHGEF38 NM_001242729.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06718737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF38	NM_001242729.2	c.245C>G	p.Pro82Arg	missense_variant	Exon 2 of 14	ENST00000420470.3	NP_001229658.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF38	ENST00000420470.3	c.245C>G	p.Pro82Arg	missense_variant	Exon 2 of 14	5	NM_001242729.2	ENSP00000416125.2
ARHGEF38	ENST00000265154.6	c.245C>G	p.Pro82Arg	missense_variant	Exon 2 of 4	1		ENSP00000265154.2
ARHGEF38	ENST00000506828.1	n.118C>G		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461740 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245C>G (p.P82R) alteration is located in exon 2 (coding exon 2) of the ARHGEF38 gene. This alteration results from a C to G substitution at nucleotide position 245, causing the proline (P) at amino acid position 82 to be replaced by an arginine (R). 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	0.071
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.078
DEOGEN2	Benign	0.0052	.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.057
Sift	Benign	0.21	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	.;B
Vest4		0.088
MutPred		0.22		Gain of glycosylation at T81 (P = 0.0135);Gain of glycosylation at T81 (P = 0.0135);
MVP		0.12
MPC		0.045
ClinPred		0.14	T
GERP RS		3.3
Varity_R		0.024
gMVP		0.094

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: chr4-106510453;