17-8312092-G-A

Variant names:

• chr17-8312092-G-A
• rs773399469
• NM_173728.4:c.53G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173728.4(ARHGEF15):​c.53G>A​(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,292,692 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 16)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34616905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 16	1	NM_173728.4	ENSP00000355026.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 1 AN: 75704 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

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: 0.0000262

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 3 AN: 150940 Hom.: 0 AF XY: 0.0000363 AC XY: 3 AN XY: 82688

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000189 AC: 23 AN: 1216988 Hom.: 0 Cov.: 36 AF XY: 0.0000271 AC XY: 16 AN XY: 591254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000547

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000514

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000173

Gnomad4 OTH exome AF: 0.0000617

GnomAD4 genome AF: 0.0000132 AC: 1 AN: 75704 Hom.: 0 Cov.: 16 AF XY: 0.0000277 AC XY: 1 AN XY: 36092

Gnomad4 AFR AF: 0.00

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: 0.0000262

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

Nov 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the ARHGEF15 protein (p.Arg18Gln). This variant is present in population databases (rs773399469, gnomAD 0.004%). 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: 1021738). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	.;T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.0	.;M;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.31	.;N;.;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Benign	0.60	T;T;T;T
Polyphen		1.0	.;D;.;D
Vest4		0.40, 0.40
MVP		0.83
MPC		0.45
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.38
gMVP		0.29

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: rs773399469; hg19: chr17-8215410;