Genetic Variant ARHGEF1:c.-19-5T>C (chr19-41888059-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004706.4(ARHGEF1):c.-19-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,611,162 control chromosomes in the GnomAD database, including 21,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 10674 hom., cov: 33)

Exomes 𝑓: 0.036 ( 10737 hom. )

Consequence

ARHGEF1
NM_004706.4 splice_region, intron

Scores

Splicing: ADA: 0.00007322

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.334

Variant links:

Genes affected

ARHGEF1 (HGNC:681): (Rho guanine nucleotide exchange factor 1) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

ARHGEF1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 19-41888059-T-C is Benign according to our data. Variant chr19-41888059-T-C is described in ClinVar as [Benign]. Clinvar id is 1165766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF1	NM_004706.4 link	c.-19-5T>C		splice_region_variant, intron_variant	Intron 1 of 28	ENST00000354532.8	NP_004697.2	Q92888-1A0A024R0R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF1	ENST00000354532.8 link	c.-19-5T>C		splice_region_variant, intron_variant	Intron 1 of 28	1	NM_004706.4	ENSP00000346532.3		Q92888-1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

32962

AN:

151908

Hom.:

10634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0861

Gnomad ASJ

AF:

0.0534

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0892

Gnomad NFE

AF:

0.00540

Gnomad OTH

AF:

0.163

GnomAD3 exomes

AF:

0.0864

AC:

21468

AN:

248560

Hom.:

4809

AF XY:

0.0755

AC XY:

10146

AN XY:

134438

show subpopulations

Gnomad AFR exome

AF:

0.712

Gnomad AMR exome

AF:

0.0446

Gnomad ASJ exome

AF:

0.0519

Gnomad EAS exome

AF:

0.201

Gnomad SAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.00487

Gnomad OTH exome

AF:

0.0461

GnomAD4 exome

AF:

0.0358

AC:

52183

AN:

1459136

Hom.:

10737

Cov.:

AF XY:

0.0357

AC XY:

25934

AN XY:

725818

show subpopulations

Gnomad4 AFR exome

AF:

0.725

Gnomad4 AMR exome

AF:

0.0488

Gnomad4 ASJ exome

AF:

0.0506

Gnomad4 EAS exome

AF:

0.155

Gnomad4 SAS exome

AF:

0.111

Gnomad4 FIN exome

AF:

0.000674

Gnomad4 NFE exome

AF:

0.00353

Gnomad4 OTH exome

AF:

0.0767

GnomAD4 genome

AF:

0.217

AC:

33064

AN:

152026

Hom.:

10674

Cov.:

AF XY:

0.213

AC XY:

15855

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.703

Gnomad4 AMR

AF:

0.0860

Gnomad4 ASJ

AF:

0.0534

Gnomad4 EAS

AF:

0.189

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00539

Gnomad4 OTH

AF:

0.170

Alfa

AF:

0.110

Hom.:

2584

Bravo

AF:

0.244

Asia WGS

AF:

0.254

AC:

884

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00772

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ARHGEF1-related disorder

Benign:1

Nov 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.8

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000073

dbscSNV1_RF

Benign

0.0040

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