17-8312119-G-C

Position:

• chr17-8312119-G-C

Variant summary

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

The NM_173728.4(ARHGEF15):​c.80G>C​(p.Arg27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000704 in 1,278,664 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38

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 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.80G>C	p.Arg27Pro	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.80G>C	p.Arg27Pro	missense_variant	2/16	1	NM_173728.4	ENSP00000355026	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182036 Hom.: 0 AF XY: 0.00000997 AC XY: 1 AN XY: 100284

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: 0.0000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000704 AC: 9 AN: 1278664 Hom.: 0 Cov.: 39 AF XY: 0.0000111 AC XY: 7 AN XY: 628156

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: 0.000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.91e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Benign	0.91
DEOGEN2	Benign	0.064	.;T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T;.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.0	.;M;.;M
MutationTaster	Benign	0.90	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.090	.;N;.;N
REVEL	Benign	0.29
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Benign	0.18	T;T;T;T
Polyphen		1.0	.;D;.;D
Vest4		0.42, 0.43
MutPred		0.41		Gain of glycosylation at R27 (P = 0.005);Gain of glycosylation at R27 (P = 0.005);Gain of glycosylation at R27 (P = 0.005);Gain of glycosylation at R27 (P = 0.005);
MVP		0.88
MPC		0.54
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.18
gMVP		0.40

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: rs199663714; hg19: chr17-8215437;