dbSNP rs114893794: ARHGEF4:p.Glu1416Glu (chr2-131038975-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001367493.1(ARHGEF4):c.4248G>A(p.Glu1416Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,738 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 8 hom. )

Consequence

ARHGEF4
NM_001367493.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.91

Publications

0 publications found

Variant links:

Genes affected

ARHGEF4 (HGNC:684): (Rho guanine nucleotide exchange factor 4) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The protein encoded by this gene may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jun 2013]

ARHGEF4 links:

SMIM39 (HGNC:54076): (small integral membrane protein 39) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM39 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 2-131038975-G-A is Benign according to our data. Variant chr2-131038975-G-A is described in ClinVar as Benign. ClinVar VariationId is 721098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.91 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00556 (847/152352) while in subpopulation AFR AF = 0.0187 (776/41596). AF 95% confidence interval is 0.0176. There are 7 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367493.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF4	NM_001367493.1	MANE Select	c.4248G>A	p.Glu1416Glu	synonymous	Exon 6 of 14	NP_001354422.1	E7EV07
ARHGEF4	NM_001375900.1		c.735G>A	p.Glu245Glu	synonymous	Exon 5 of 13	NP_001362829.1
ARHGEF4	NM_015320.4		c.690G>A	p.Glu230Glu	synonymous	Exon 7 of 15	NP_056135.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF4	ENST00000409359.7	TSL:5 MANE Select	c.4248G>A	p.Glu1416Glu	synonymous	Exon 6 of 14	ENSP00000386794.3	E7EV07
ARHGEF4	ENST00000392953.8	TSL:1	c.762G>A	p.Glu254Glu	synonymous	Exon 5 of 12	ENSP00000376680.5	A0A0C4DFY6
ARHGEF4	ENST00000355771.7	TSL:1	c.477G>A	p.Glu159Glu	synonymous	Exon 3 of 11	ENSP00000348017.3	Q9NR80-3

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0187

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00159

AC:

398

AN:

250530

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.0205

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.000997

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000607

AC:

887

AN:

1461386

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

361

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.0192

AC:

644

AN:

33480

American (AMR)

AF:

0.00110

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

52988

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000647

AC:

AN:

1111970

Other (OTH)

AF:

0.00152

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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

AF:

0.00556

AC:

847

AN:

152352

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

395

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0187

AC:

776

AN:

41596

American (AMR)

AF:

0.00346

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68024

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00625

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

ARHGEF4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.9

(source)

DANN

Benign

0.68

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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