17-8312077-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173728.4(ARHGEF15):c.38C>G(p.Thr13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,418,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. T13M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000076 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13918671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.38C>G	p.Thr13Arg	missense_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.38C>G	p.Thr13Arg	missense_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000761 AC: 11 AN: 144640 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000504

GnomAD3 exomes AF: 0.0000379 AC: 8 AN: 211030 Hom.: 0 AF XY: 0.0000351 AC XY: 4 AN XY: 113944

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000642

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 31 AN: 1273380 Hom.: 0 Cov.: 35 AF XY: 0.0000205 AC XY: 13 AN XY: 633068

Gnomad4 AFR exome AF: 0.000802

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000835

Gnomad4 SAS exome AF: 0.0000260

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.98e-7

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.0000761 AC: 11 AN: 144640 Hom.: 0 Cov.: 23 AF XY: 0.0000854 AC XY: 6 AN XY: 70236

Gnomad4 AFR AF: 0.000257

Gnomad4 AMR AF: 0.00

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: 0.000504

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 18, 2023

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 tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 648853). This variant has not been reported in the literature in individuals affected with ARHGEF15-related conditions. This variant is present in population databases (rs373751727, gnomAD 0.05%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 13 of the ARHGEF15 protein (p.Thr13Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Benign	0.87
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.0066
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T;.;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.039	D;D;T;D
Polyphen		0.66	.;P;.;P
Vest4		0.38, 0.38
MutPred		0.31		Loss of phosphorylation at T13 (P = 0.0024);Loss of phosphorylation at T13 (P = 0.0024);Loss of phosphorylation at T13 (P = 0.0024);Loss of phosphorylation at T13 (P = 0.0024);
MVP		0.75
MPC		0.19
ClinPred		0.18	T
GERP RS		3.8
Varity_R		0.22
gMVP		0.39

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: rs373751727; hg19: chr17-8215395;