rs1060500049

chr17-8313546-T-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.980T>C(p.Val327Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.443

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=0.041617513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.980T>C	p.Val327Ala	missense_variant	4/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.980T>C	p.Val327Ala	missense_variant	4/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Aug 28, 2016

This sequence change replaces valine with alanine at codon 327 of the ARHGEF15 protein (p.Val327Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. 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 alanine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ARHGEF15-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.3
Dann	Benign	0.36
DEOGEN2	Benign	0.059	T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.62	N;N;.
REVEL	Benign	0.064
Sift	Benign	0.12	T;T;.
Sift4G	Benign	0.46	T;T;.
Polyphen		0.0020	B;B;.
Vest4		0.033
MutPred		0.15		Gain of glycosylation at P324 (P = 0.1164);Gain of glycosylation at P324 (P = 0.1164);.;
MVP		0.17
MPC		0.10
ClinPred		0.070	T
GERP RS		-3.7
Varity_R		0.081
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060500049; hg19: chr17-8216864;