rs138484229

chr17-8312093-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_173728.4(ARHGEF15):c.54G>A(p.Arg18=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,412,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.381

Genes affected

ARHGEF15 (HGNC:15590): (Rho guanine nucleotide exchange factor 15) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-8312093-G-A is Benign according to our data. Variant chr17-8312093-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 530551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.381 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.54G>A	p.Arg18=	synonymous_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.54G>A	p.Arg18=	synonymous_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 239 AN: 112422 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000619

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000182

Gnomad OTH AF: 0.000700

GnomAD3 exomes AF: 0.000380 AC: 63 AN: 165958 Hom.: 0 AF XY: 0.000220 AC XY: 20 AN XY: 90704

Gnomad AFR exome AF: 0.00526

Gnomad AMR exome AF: 0.000107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 190 AN: 1300260 Hom.: 0 Cov.: 36 AF XY: 0.000120 AC XY: 77 AN XY: 640268

Gnomad4 AFR exome AF: 0.00582

Gnomad4 AMR exome AF: 0.000135

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: 0.00000292

Gnomad4 OTH exome AF: 0.000380

GnomAD4 genome AF: 0.00213 AC: 240 AN: 112438 Hom.: 0 Cov.: 19 AF XY: 0.00192 AC XY: 103 AN XY: 53780

Gnomad4 AFR AF: 0.00829

Gnomad4 AMR AF: 0.000619

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000182

Gnomad4 OTH AF: 0.000697

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00206

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ARHGEF15: BP4, BP7 -

ARHGEF15-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	11
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs138484229; hg19: chr17-8215411; COSMIC: COSV100730144; COSMIC: COSV100730144;