rs142667369

chr17-8316081-G-Achr17-8316081-G-Cchr17-8316081-G-T

Variant summary

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

The NM_173728.4(ARHGEF15):c.1637G>A(p.Arg546Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,450,688 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58

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	UniProt
ARHGEF15	NM_173728.4	c.1637G>A	p.Arg546Gln	missense_variant	9/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.1637G>A	p.Arg546Gln	missense_variant	9/16	1	NM_173728.4	P1
ARHGEF15	ENST00000421050.2	c.1637G>A	p.Arg546Gln	missense_variant	9/16	1		P1
ARHGEF15	ENST00000647883.1	c.1100G>A	p.Arg367Gln	missense_variant	6/13

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000128 AC: 3 AN: 234688 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000885

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450688 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000675

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Uncertain	0.32
Sift	Benign	0.040	D;D;.
Sift4G	Uncertain	0.017	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.52
MutPred		0.53		Gain of ubiquitination at K543 (P = 0.0544);Gain of ubiquitination at K543 (P = 0.0544);.;
MVP		0.78
MPC		1.9
ClinPred		0.92	D
GERP RS		3.7
Varity_R		0.25
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142667369; hg19: chr17-8219399;