rs202178259

Variant names:

• chr17-8320860-C-A
• rs202178259
• NM_173728.4:c.2393C>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_173728.4(ARHGEF15):​c.2393C>A​(p.Pro798His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.06

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0698936).
• BP6: Variant 17-8320860-C-A is Benign according to our data. Variant chr17-8320860-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.2393C>A	p.Pro798His	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.2393C>A	p.Pro798His	missense_variant	Exon 16 of 16	1	NM_173728.4	ENSP00000355026.3
ARHGEF15	ENST00000421050.2	c.2393C>A	p.Pro798His	missense_variant	Exon 16 of 16	1		ENSP00000412505.1
ARHGEF15	ENST00000647883.1	c.1856C>A	p.Pro619His	missense_variant	Exon 13 of 13			ENSP00000498197.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251216 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135792

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460726 Hom.: 0 Cov.: 53 AF XY: 0.0000261 AC XY: 19 AN XY: 726668

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000270

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152234 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74434

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000280

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2393C>A (p.P798H) alteration is located in exon 16 (coding exon 15) of the ARHGEF15 gene. This alteration results from a C to A substitution at nucleotide position 2393, causing the proline (P) at amino acid position 798 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Benign	0.037	T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.9	N;N;.
REVEL	Benign	0.27
Sift	Benign	0.093	T;T;.
Sift4G	Benign	0.14	T;T;.
Polyphen		0.016	B;B;.
Vest4		0.21
MVP		0.73
MPC		0.19
ClinPred		0.063	T
GERP RS		3.6
Varity_R		0.079
gMVP		0.33

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: rs202178259; hg19: chr17-8224178;