rs112463375

Positions:

• chr17-8320930-G-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.2463G>C​(p.Gln821His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,614,014 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75

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=0.009857684).
• BP6: Variant 17-8320930-G-C is Benign according to our data. Variant chr17-8320930-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 412667.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/exons	MANE	Protein	UniProt
ARHGEF15	NM_173728.4	c.2463G>C	p.Gln821His	missense_variant	16/16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.2463G>C	p.Gln821His	missense_variant	16/16	1	NM_173728.4	ENSP00000355026.3
ARHGEF15	ENST00000421050.2	c.2463G>C	p.Gln821His	missense_variant	16/16	1		ENSP00000412505.1
ARHGEF15	ENST00000647883.1	c.1926G>C	p.Gln642His	missense_variant	13/13			ENSP00000498197.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152158 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000278 AC: 70 AN: 251464 Hom.: 1 AF XY: 0.000228 AC XY: 31 AN XY: 135920

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461738 Hom.: 2 Cov.: 53 AF XY: 0.000144 AC XY: 105 AN XY: 727166

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.000940 AC XY: 70 AN XY: 74436

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.000458

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: 0.000949

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.00126

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	0.018
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.60	.;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0099	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		0.61	P;P;.
Vest4		0.14
MutPred		0.23		Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);.;
MVP		0.67
MPC		0.22
ClinPred		0.058	T
GERP RS		3.9
Varity_R		0.26
gMVP		0.55

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: rs112463375; hg19: chr17-8224248;