19-41888066-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004706.4(ARHGEF1):c.-17C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,612,660 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 6 hom. )

Consequence

ARHGEF1
NM_004706.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.505

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004104078).

BP6

Variant 19-41888066-C-T is Benign according to our data. Variant chr19-41888066-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1050715.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF1	NM_004706.4 link	c.-17C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 29	ENST00000354532.8	NP_004697.2	Q92888-1A0A024R0R1
ARHGEF1	NM_004706.4 link	c.-17C>T	splice_region_variant	Exon 2 of 29	ENST00000354532.8	NP_004697.2	Q92888-1A0A024R0R1
ARHGEF1	NM_004706.4 link	c.-17C>T	5_prime_UTR_variant	Exon 2 of 29	ENST00000354532.8	NP_004697.2	Q92888-1A0A024R0R1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARHGEF1	ENST00000354532 link	c.-17C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 29	1	NM_004706.4	ENSP00000346532.3	Q92888-1
ARHGEF1	ENST00000354532.8 link	c.-17C>T	splice_region_variant	Exon 2 of 29	1	NM_004706.4	ENSP00000346532.3	Q92888-1
ARHGEF1	ENST00000354532 link	c.-17C>T	5_prime_UTR_variant	Exon 2 of 29	1	NM_004706.4	ENSP00000346532.3	Q92888-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000560

AC:

140

AN:

249838

Hom.:

AF XY:

0.000785

AC XY:

106

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00451

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000270

AC:

395

AN:

1460354

Hom.:

Cov.:

AF XY:

0.000387

AC XY:

281

AN XY:

726472

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00426

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000190

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000419

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ARHGEF1 p.Pro10Leu variant was identified in dbSNP (ID: rs545895111) but was not identified in ClinVar, Clinvitae, Cosmic, or LOVD 3.0, nor identified in the literature. The variant was identified in control databases in 140 of 249838 chromosomes at a frequency of 0.00056, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the South Asian population in 138 of 30590 chromosomes (freq: 0.004511) and the European (non-Finnish) population in 2 of 112612 chromosomes (freq: 0.000018), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or other populations. The p.Pro10 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.60

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.77

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.087

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.83

.;P

Vest4

0.27

MutPred

0.17

Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);

MVP

0.48

MPC

0.44

ClinPred

0.14

GERP RS

2.7

gMVP

0.18

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