rs1060500051

Positions:

• chr17-8318654-A-G

Variant summary

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

The NM_173728.4(ARHGEF15):​c.1864A>G​(p.Lys622Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.1864A>G	p.Lys622Glu	missense_variant	11/16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.1864A>G	p.Lys622Glu	missense_variant	11/16	1	NM_173728.4	ENSP00000355026	P1
ARHGEF15	ENST00000421050.2	c.1864A>G	p.Lys622Glu	missense_variant	11/16	1		ENSP00000412505	P1
	ENST00000458568.1	n.59T>C		non_coding_transcript_exon_variant	1/2	3
ARHGEF15	ENST00000647883.1	c.1327A>G	p.Lys443Glu	missense_variant	8/13			ENSP00000498197

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461082 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726706

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2016

This sequence change replaces lysine with glutamic acid at codon 622 of the ARHGEF15 protein (p.Lys622Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	1.0	N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.14	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.52
MutPred		0.48		Loss of ubiquitination at K622 (P = 0.0326);Loss of ubiquitination at K622 (P = 0.0326);.;
MVP		0.90
MPC		0.62
ClinPred		0.77	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.82

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: rs1060500051; hg19: chr17-8221972;