Genetic Variant ARHGEF37:p.Arg59His (chr5-149597945-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001001669.3(ARHGEF37):c.176G>A(p.Arg59His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,588,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

ARHGEF37
NM_001001669.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0340

Publications

1 publications found

Variant links:

Genes affected

ARHGEF37 (HGNC:34430): (Rho guanine nucleotide exchange factor 37) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF37 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012870073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF37	NM_001001669.3 link	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 13	ENST00000333677.7	NP_001001669.2	A1IGU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF37	ENST00000333677.7 link	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 13	2	NM_001001669.3	ENSP00000328083.6		A1IGU5
ARHGEF37	ENST00000505810.5 link	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 3	5		ENSP00000425621.1		D6RJH4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

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

GnomAD2 exomes

AF:

0.000140

AC:

AN:

206780

AF XY:

0.000142

show subpopulations

Gnomad AFR exome

AF:

0.0000833

Gnomad AMR exome

AF:

0.000143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000430

Gnomad OTH exome

AF:

0.000397

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1436348

Hom.:

Cov.:

AF XY:

0.0000393

AC XY:

AN XY:

712916

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32530

American (AMR)

AF:

0.000124

AC:

AN:

40308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25548

East Asian (EAS)

AF:

0.000734

AC:

AN:

38142

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81982

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1100468

Other (OTH)

AF:

0.000118

AC:

AN:

59490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41534

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000414

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0036

.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L

PhyloP100

0.034

PrimateAI

Benign

0.20

PROVEAN

Benign

2.3

N;N

REVEL

Benign

0.13

Sift

Benign

0.58

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0070

.;B

Vest4

0.11

MVP

0.067

MPC

0.12

ClinPred

0.021

GERP RS

-0.045

Varity_R

0.051

gMVP

0.10

Mutation Taster

=87/13

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

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5-149597945-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over