rs9890841

chr17-8312256-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173728.4(ARHGEF15):c.217C>T(p.Pro73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,454,904 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 24)
  • Exomes 𝑓: 0.0016 (49 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.81

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029857159).
• BP6: Variant 17-8312256-C-T is Benign according to our data. Variant chr17-8312256-C-T is described in ClinVar as [Benign]. Clinvar id is 412670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.217C>T	p.Pro73Ser	missense_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.217C>T	p.Pro73Ser	missense_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2086 AN: 145418 Hom.: 52 Cov.: 24

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00454

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000121

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00407 AC: 853 AN: 209654 Hom.: 21 AF XY: 0.00320 AC XY: 356 AN XY: 111384

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000460

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00162 AC: 2115 AN: 1309364 Hom.: 49 Cov.: 36 AF XY: 0.00139 AC XY: 896 AN XY: 646818

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.00252

Gnomad4 ASJ exome AF: 0.0000540

Gnomad4 EAS exome AF: 0.0000283

Gnomad4 SAS exome AF: 0.0000785

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0144 AC: 2089 AN: 145540 Hom.: 53 Cov.: 24 AF XY: 0.0138 AC XY: 978 AN XY: 70734

Gnomad4 AFR AF: 0.0500

Gnomad4 AMR AF: 0.00453

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000121

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00262 Hom.: 8

Bravo AF: 0.0159

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00437 AC: 530

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	23
Dann	Benign	0.91
Eigen	Benign	-0.023
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;.;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.37	T
Sift4G	Uncertain	0.044	D;T;T;T
Polyphen		0.32	.;B;.;B
Vest4		0.30, 0.29
MVP		0.76
MPC		0.46
ClinPred		0.019	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.19

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: rs9890841; hg19: chr17-8215574;