Genetic Variant ARHGEF35:p.Glu343Lys (chr7-144187357-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001003702.3(ARHGEF35):c.1027G>A(p.Glu343Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000032 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000017 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF35
NM_001003702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.51

Variant links:

Genes affected

ARHGEF35 (HGNC:33846): (Rho guanine nucleotide exchange factor 35)

ARHGEF35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07489005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF35	NM_001003702.3 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 2 of 2	ENST00000378115.3	NP_001003702.2	A5YM69
ARHGEF35	NM_001368318.1 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 2 of 2		NP_001355247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF35	ENST00000378115.3 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 2 of 2	1	NM_001003702.3	ENSP00000367355.3		A5YM69
ARHGEF35	ENST00000688754.1 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 2 of 2			ENSP00000510684.1		A5YM69

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

124800

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000669

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000174

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000174

AC:

AN:

1323548

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

662016

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000231

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000320

AC:

AN:

124886

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

60186

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000671

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000174

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1027G>A (p.E343K) alteration is located in exon 2 (coding exon 1) of the ARHGEF35 gene. This alteration results from a G to A substitution at nucleotide position 1027, causing the glutamic acid (E) at amino acid position 343 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.41

DANN

Benign

0.54

DEOGEN2

Benign

0.028

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.56

M_CAP

Benign

0.0018

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PROVEAN

Benign

-1.2

REVEL

Benign

0.082

Sift

Benign

0.60

Sift4G

Pathogenic

0.0

Polyphen

0.93

Vest4

0.091

MutPred

0.24

Gain of ubiquitination at E343 (P = 6e-04);

MVP

0.040

MPC

1.3

ClinPred

0.13

GERP RS

-0.67

Varity_R

0.039

gMVP

0.019

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