19-41888059-T-C

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

2
Splicing: ADA: 0.00007322
2

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]

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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
ARHGEF1NM_004706.4 linkc.-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
ARHGEF1ENST00000354532.8 linkc.-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.:
33
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.:
32
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.:
33
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.

Other links and lift over

dbSNP: rs28396197; hg19: chr19-42392130; COSMIC: COSV61526779; COSMIC: COSV61526779; API