Genetic Variant ARHGEF35:p.Gly467Asp (chr7-144186984-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001003702.3(ARHGEF35):c.1400G>A(p.Gly467Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,399,798 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000011 ( 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: -0.755

Publications

0 publications found

Variant links:

Genes affected

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

ARHGEF35 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05433157).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003702.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF35	NM_001003702.3	MANE Select	c.1400G>A	p.Gly467Asp	missense	Exon 2 of 2	NP_001003702.2	A5YM69
	ARHGEF35	NM_001368318.1		c.1400G>A	p.Gly467Asp	missense	Exon 2 of 2	NP_001355247.1	A5YM69

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF35	ENST00000378115.3	TSL:1 MANE Select	c.1400G>A	p.Gly467Asp	missense	Exon 2 of 2	ENSP00000367355.3	A5YM69
ARHGEF35	ENST00000688754.1		c.1400G>A	p.Gly467Asp	missense	Exon 2 of 2	ENSP00000510684.1	A5YM69
ARHGEF35	ENST00000852510.1		c.1400G>A	p.Gly467Asp	missense	Exon 3 of 3	ENSP00000522569.1

Frequencies

GnomAD3 genomes

AF:

0.0000278

AC:

AN:

143688

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000625

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000836

AC:

AN:

239266

AF XY:

0.0000154

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1399798

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

696890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32276

American (AMR)

AF:

0.00

AC:

AN:

43842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25666

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

85672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.0000142

AC:

AN:

1058426

Other (OTH)

AF:

0.00

AC:

AN:

58288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000278

AC:

AN:

143688

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

70074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38802

American (AMR)

AF:

0.00

AC:

AN:

14686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000625

AC:

AN:

64040

Other (OTH)

AF:

0.00

AC:

AN:

1980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000847

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.12

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.039

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.38

M_CAP

Benign

0.0015

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.11

PhyloP100

-0.76

PROVEAN

Benign

-0.51

REVEL

Benign

0.0030

Sift

Benign

0.56

Sift4G

Benign

0.48

Polyphen

0.016

Vest4

0.050

MVP

0.085

MPC

1.5

ClinPred

0.0071

GERP RS

-2.0

Varity_R

0.031

gMVP

0.0099

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over