Genetic Variant ARHGEF35:p.Gly316Arg (chr7-144187438-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001003702.3(ARHGEF35):c.946G>C(p.Gly316Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF35
NM_001003702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0810

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0740197).

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.946G>C	p.Gly316Arg	missense	Exon 2 of 2	NP_001003702.2	A5YM69
	ARHGEF35	NM_001368318.1		c.946G>C	p.Gly316Arg	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.946G>C	p.Gly316Arg	missense	Exon 2 of 2	ENSP00000367355.3	A5YM69
ARHGEF35	ENST00000688754.1		c.946G>C	p.Gly316Arg	missense	Exon 2 of 2	ENSP00000510684.1	A5YM69
ARHGEF35	ENST00000852510.1		c.946G>C	p.Gly316Arg	missense	Exon 3 of 3	ENSP00000522569.1

Frequencies

GnomAD3 genomes

AF:

0.0000558

AC:

AN:

107454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000226

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

915384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

466412

African (AFR)

AF:

0.00

AC:

AN:

23278

American (AMR)

AF:

0.00

AC:

AN:

27098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21120

East Asian (EAS)

AF:

0.00

AC:

AN:

33176

South Asian (SAS)

AF:

0.00

AC:

AN:

60926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2974

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

658428

Other (OTH)

AF:

0.00

AC:

AN:

41290

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000558

AC:

AN:

107514

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

50988

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000225

AC:

AN:

26620

American (AMR)

AF:

0.00

AC:

AN:

10832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3126

East Asian (EAS)

AF:

0.00

AC:

AN:

4000

South Asian (SAS)

AF:

0.00

AC:

AN:

3012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51464

Other (OTH)

AF:

0.00

AC:

AN:

1454

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000848111), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

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.:

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

0.33

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.8

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.62

M_CAP

Benign

0.0016

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

-0.081

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.019

Sift

Benign

0.033

Sift4G

Benign

0.44

Polyphen

0.40

Vest4

0.051

MutPred

0.22

Loss of loop (P = 0.0073)

MVP

0.25

MPC

1.8

ClinPred

0.12

GERP RS

-3.4

Varity_R

0.15

gMVP

0.0051

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over