Variant 19-7376751-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001367823.1(ARHGEF18):c.535G>C(p.Val179Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,234,244 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0061 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 73 hom. )

Consequence

ARHGEF18
NM_001367823.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.11

Variant links:

Genes affected

ARHGEF18 (HGNC:17090): (Rho/Rac guanine nucleotide exchange factor 18) Rho GTPases are GTP binding proteins that regulate a wide spectrum of cellular functions. These cellular processes include cytoskeletal rearrangements, gene transcription, cell growth and motility. Activation of Rho GTPases is under the direct control of guanine nucleotide exchange factors (GEFs). The protein encoded by this gene is a guanine nucleotide exchange factor and belongs to the Rho GTPase GEF family. Family members share a common feature, a Dbl (DH) homology domain followed by a pleckstrin (PH) homology domain. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2018]

ARHGEF18 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004850179).

BP6

Variant 19-7376751-G-C is Benign according to our data. Variant chr19-7376751-G-C is described in ClinVar as [Benign]. Clinvar id is 2649155.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0061 (929/152360) while in subpopulation NFE AF= 0.0104 (705/68018). AF 95% confidence interval is 0.00973. There are 7 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF18	NM_001367823.1 linkuse as main transcript	c.535G>C	p.Val179Leu	missense_variant	5/29	ENST00000668164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF18	ENST00000668164.2 linkuse as main transcript	c.535G>C	p.Val179Leu	missense_variant	5/29		NM_001367823.1	A2	Q6ZSZ5-4
ARHGEF18	ENST00000671891.2 linkuse as main transcript	c.730G>C	p.Val244Leu	missense_variant	5/10

Frequencies

GnomAD3 genomes

AF:

0.00610

AC:

929

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00825

AC:

AN:

6548

Hom.:

AF XY:

0.00913

AC XY:

AN XY:

3176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00495

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00939

Gnomad OTH exome

AF:

0.00649

GnomAD4 exome

AF:

0.0115

AC:

12487

AN:

1081884

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

5819

AN XY:

510830

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.00375

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000562

Gnomad4 FIN exome

AF:

0.00144

Gnomad4 NFE exome

AF:

0.0130

Gnomad4 OTH exome

AF:

0.00862

GnomAD4 genome

AF:

0.00610

AC:

929

AN:

152360

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

428

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00250

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.0104

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00736

Hom.:

Bravo

AF:

0.00643

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0138

AC:

ExAC

AF:

0.00202

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

ARHGEF18: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.9

DANN

Benign

0.92

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0049

Sift4G

Benign

0.31

Vest4

0.092

MVP

0.22

GERP RS

2.4

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over