rs115597604

Variant names:

• chr17-8320961-T-C
• rs115597604
• NM_173728.4:c.2494T>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173728.4(ARHGEF15):​c.2494T>C​(p.Ser832Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,613,936 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.66

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014302611).
• BP6: Variant 17-8320961-T-C is Benign according to our data. Variant chr17-8320961-T-C is described in ClinVar as [Benign]. Clinvar id is 461434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.2494T>C	p.Ser832Pro	missense_variant	Exon 16 of 16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.2494T>C	p.Ser832Pro	missense_variant	Exon 16 of 16	1	NM_173728.4	ENSP00000355026.3
ARHGEF15	ENST00000421050.2	c.2494T>C	p.Ser832Pro	missense_variant	Exon 16 of 16	1		ENSP00000412505.1
ARHGEF15	ENST00000647883.1	c.1957T>C	p.Ser653Pro	missense_variant	Exon 13 of 13			ENSP00000498197.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000517 AC: 130 AN: 251432 Hom.: 1 AF XY: 0.000324 AC XY: 44 AN XY: 135914

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.000434

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: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000246 AC: 359 AN: 1461742 Hom.: 4 Cov.: 33 AF XY: 0.000219 AC XY: 159 AN XY: 727176

Gnomad4 AFR exome AF: 0.00729

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74406

Gnomad4 AFR AF: 0.00648

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000729 Hom.: 0

Bravo AF: 0.00229

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T;T;.
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.65	.;T;T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.84	N;N;.
REVEL	Benign	0.29
Sift	Uncertain	0.010	D;D;.
Sift4G	Benign	0.18	T;T;.
Polyphen		0.99	D;D;.
Vest4		0.23
MVP		0.78
MPC		0.29
ClinPred		0.023	T
GERP RS		4.1
Varity_R		0.34
gMVP		0.45

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: rs115597604; hg19: chr17-8224279;