17-8316081-G-C

Variant names:

• chr17-8316081-G-C
• rs142667369
• NM_173728.4:c.1637G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_173728.4(ARHGEF15):​c.1637G>C​(p.Arg546Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00125 in 1,602,988 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.076511025).
• BP6: Variant 17-8316081-G-C is Benign according to our data. Variant chr17-8316081-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 461427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.1637G>C	p.Arg546Pro	missense_variant	Exon 9 of 16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.1637G>C	p.Arg546Pro	missense_variant	Exon 9 of 16	1	NM_173728.4	ENSP00000355026.3
ARHGEF15	ENST00000421050.2	c.1637G>C	p.Arg546Pro	missense_variant	Exon 9 of 16	1		ENSP00000412505.1
ARHGEF15	ENST00000647883.1	c.1100G>C	p.Arg367Pro	missense_variant	Exon 6 of 13			ENSP00000498197.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152182 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000712 AC: 167 AN: 234688 Hom.: 0 AF XY: 0.000752 AC XY: 97 AN XY: 128918

Gnomad AFR exome AF: 0.000544

Gnomad AMR exome AF: 0.0000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000663

Gnomad FIN exome AF: 0.000275

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000683

GnomAD4 exome AF: 0.00129 AC: 1865 AN: 1450688 Hom.: 2 Cov.: 33 AF XY: 0.00125 AC XY: 903 AN XY: 721996

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000900

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.000227

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.000598

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152300 Hom.: 0 Cov.: 31 AF XY: 0.000980 AC XY: 73 AN XY: 74468

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000790

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000583 AC: 5

ExAC AF: 0.000685 AC: 83

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;.
Eigen	Benign	0.089
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	.;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.7	D;D;.
REVEL	Uncertain	0.33
Sift	Benign	0.081	T;T;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.064	B;B;.
Vest4		0.66
MVP		0.72
MPC		1.6
ClinPred		0.087	T
GERP RS		3.7
Varity_R		0.75
gMVP		0.79

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: rs142667369; hg19: chr17-8219399;