rs375343071

chr17-8312305-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173728.4(ARHGEF15):c.266C>A(p.Thr89Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000692 in 1,560,656 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T89T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000060 (3 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.145

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05725369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.266C>A	p.Thr89Asn	missense_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.266C>A	p.Thr89Asn	missense_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes AF: 0.000154 AC: 23 AN: 149774 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000996

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000796

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000976

GnomAD3 exomes AF: 0.0000424 AC: 9 AN: 212278 Hom.: 0 AF XY: 0.0000177 AC XY: 2 AN XY: 112756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000396

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000197

GnomAD4 exome AF: 0.0000602 AC: 85 AN: 1410882 Hom.: 3 Cov.: 36 AF XY: 0.0000488 AC XY: 34 AN XY: 697116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000254

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000515

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000276

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000154 AC: 23 AN: 149774 Hom.: 0 Cov.: 28 AF XY: 0.0000685 AC XY: 5 AN XY: 72990

Gnomad4 AFR AF: 0.0000246

Gnomad4 AMR AF: 0.000996

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000796

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000976

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000742 AC: 9

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.266C>A (p.T89N) alteration is located in exon 2 (coding exon 1) of the ARHGEF15 gene. This alteration results from a C to A substitution at nucleotide position 266, causing the threonine (T) at amino acid position 89 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 89 of the ARHGEF15 protein (p.Thr89Asn). This variant is present in population databases (rs375343071, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 403967). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Benign	0.87
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.52	T;.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.093	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.076, 0.075
MVP		0.68
MPC		0.14
ClinPred		0.31	T
GERP RS		4.0
Varity_R		0.093
gMVP		0.26

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: rs375343071; hg19: chr17-8215623;