rs199663714

chr17-8312119-G-Achr17-8312119-G-C

Variant summary

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

The NM_173728.4(ARHGEF15):c.80G>A(p.Arg27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,379,258 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.38

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 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=0.030038357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.80G>A	p.Arg27His	missense_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.80G>A	p.Arg27His	missense_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes AF: 0.000457 AC: 46 AN: 100590 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00546

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: 0.00

Gnomad OTH AF: 0.00154

GnomAD3 exomes AF: 0.0000494 AC: 9 AN: 182036 Hom.: 0 AF XY: 0.0000299 AC XY: 3 AN XY: 100284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000195

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: 0.0000114

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.0000305 AC: 39 AN: 1278664 Hom.: 0 Cov.: 39 AF XY: 0.0000223 AC XY: 14 AN XY: 628156

Gnomad4 AFR exome AF: 0.0000360

Gnomad4 AMR exome AF: 0.000831

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: 0.00000297

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.000457 AC: 46 AN: 100594 Hom.: 0 Cov.: 20 AF XY: 0.000489 AC XY: 23 AN XY: 47044

Gnomad4 AFR AF: 0.0000815

Gnomad4 AMR AF: 0.00545

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00153

Alfa AF: 0.0000454 Hom.: 0

Bravo AF: 0.000797

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 27 of the ARHGEF15 protein (p.Arg27His). This variant is present in population databases (rs199663714, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ARHGEF15-related conditions. ClinVar contains an entry for this variant (Variation ID: 461440). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	27
Dann	Uncertain	0.98
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.075	T;D;T;D
Polyphen		1.0	.;D;.;D
Vest4		0.39, 0.40
MVP		0.87
MPC		0.50
ClinPred		0.27	T
GERP RS		5.0
Varity_R		0.10
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs199663714; hg19: chr17-8215437;