rs777250745

Positions:

• chr17-8312379-C-A
• chr17-8312379-C-G
• chr17-8312379-C-T

Variant summary

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

The NM_173728.4(ARHGEF15):​c.340C>A​(p.Pro114Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,544 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.377

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]

ARHGEF15 (HGNC:):

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=0.1362488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.340C>A	p.Pro114Thr	missense_variant	2/16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.340C>A	p.Pro114Thr	missense_variant	2/16	1	NM_173728.4	ENSP00000355026.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245158 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

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: 0.00000137 AC: 2 AN: 1456544 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 724456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.063	.;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.46	T;.;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	.;L;.;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	.;N;.;N
REVEL	Benign	0.089
Sift	Uncertain	0.0080	.;D;.;D
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.099	.;B;.;B
Vest4		0.25, 0.25
MutPred		0.30		Gain of phosphorylation at P114 (P = 0.002);Gain of phosphorylation at P114 (P = 0.002);Gain of phosphorylation at P114 (P = 0.002);Gain of phosphorylation at P114 (P = 0.002);
MVP		0.76
MPC		0.11
ClinPred		0.12	T
GERP RS		2.6
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: rs777250745; hg19: chr17-8215697;