rs199691980

Positions:

• chr17-8315281-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173728.4(ARHGEF15):​c.1260+4G>A variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00163 in 1,612,698 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (24 hom.)
• Consequence: ARHGEF15 NM_173728.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00003177
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.31

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-8315281-G-A is Benign according to our data. Variant chr17-8315281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.1260+4G>A		splice_donor_region_variant, intron_variant		ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.1260+4G>A		splice_donor_region_variant, intron_variant		1	NM_173728.4	ENSP00000355026	P1
ARHGEF15	ENST00000421050.2	c.1260+4G>A		splice_donor_region_variant, intron_variant		1		ENSP00000412505	P1
ARHGEF15	ENST00000647883.1	c.723+4G>A		splice_donor_region_variant, intron_variant				ENSP00000498197
ARHGEF15	ENST00000578286.1	n.308+4G>A		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152118 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00252 AC: 624 AN: 247896 Hom.: 9 AF XY: 0.00326 AC XY: 439 AN XY: 134568

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.000670

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00168 AC: 2447 AN: 1460462 Hom.: 24 Cov.: 33 AF XY: 0.00208 AC XY: 1509 AN XY: 726492

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.000838

Gnomad4 NFE exome AF: 0.000857

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152236 Hom.: 1 Cov.: 31 AF XY: 0.00136 AC XY: 101 AN XY: 74442

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000949 Hom.: 1

Bravo AF: 0.000808

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 15, 2015

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

ARHGEF15-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

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

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.11
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

LitVar

Other links and lift over

dbSNP: rs199691980; hg19: chr17-8218599;