dbSNP rs4629585: ARHGEF37:p.Met421Leu (chr5-149621988-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001001669.3(ARHGEF37):c.1261A>C(p.Met421Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,613,668 control chromosomes in the GnomAD database, including 123,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.39 ( 11640 hom., cov: 33)

Exomes 𝑓: 0.39 ( 112018 hom. )

Consequence

ARHGEF37
NM_001001669.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.136

Publications

36 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2713671E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF37	NM_001001669.3 link	c.1261A>C	p.Met421Leu	missense_variant	Exon 9 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.1261A>C	p.Met421Leu	missense_variant	Exon 9 of 13	2	NM_001001669.3	ENSP00000328083.6		A1IGU5

Frequencies

GnomAD3 genomes

AF:

0.389

AC:

59056

AN:

151972

Hom.:

11630

Cov.:

show subpopulations

Gnomad AFR

AF:

0.384

Gnomad AMI

AF:

0.506

Gnomad AMR

AF:

0.452

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.514

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.369

Gnomad OTH

AF:

0.367

GnomAD2 exomes

AF:

0.417

AC:

103500

AN:

248334

AF XY:

0.414

show subpopulations

Gnomad AFR exome

AF:

0.388

Gnomad AMR exome

AF:

0.533

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.504

Gnomad FIN exome

AF:

0.353

Gnomad NFE exome

AF:

0.370

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.387

AC:

565478

AN:

1461578

Hom.:

112018

Cov.:

AF XY:

0.389

AC XY:

283014

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.385

AC:

12879

AN:

33478

American (AMR)

AF:

0.525

AC:

23419

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

8019

AN:

26134

East Asian (EAS)

AF:

0.518

AC:

20575

AN:

39692

South Asian (SAS)

AF:

0.506

AC:

43617

AN:

86246

European-Finnish (FIN)

AF:

0.361

AC:

19283

AN:

53404

Middle Eastern (MID)

AF:

0.294

AC:

1693

AN:

5766

European-Non Finnish (NFE)

AF:

0.371

AC:

413002

AN:

1111826

Other (OTH)

AF:

0.381

AC:

22991

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

21560

43120

64681

86241

107801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13272

26544

39816

53088

66360

<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:

0.389

AC:

59114

AN:

152090

Hom.:

11640

Cov.:

AF XY:

0.393

AC XY:

29216

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.385

AC:

15969

AN:

41506

American (AMR)

AF:

0.453

AC:

6917

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

1087

AN:

3472

East Asian (EAS)

AF:

0.517

AC:

2674

AN:

5168

South Asian (SAS)

AF:

0.512

AC:

2472

AN:

4824

European-Finnish (FIN)

AF:

0.345

AC:

3642

AN:

10570

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.369

AC:

25051

AN:

67970

Other (OTH)

AF:

0.368

AC:

775

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1921

3842

5763

7684

9605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.375

Hom.:

41084

Bravo

AF:

0.396

TwinsUK

AF:

0.363

AC:

1346

ALSPAC

AF:

0.367

AC:

1416

ESP6500AA

AF:

0.381

AC:

1617

ESP6500EA

AF:

0.355

AC:

3010

ExAC

AF:

0.414

AC:

50168

Asia WGS

AF:

0.498

AC:

1732

AN:

3478

EpiCase

AF:

0.360

EpiControl

AF:

0.351

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.6

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.0043

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.26

MetaRNN

Benign

0.00013

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-3.1

PhyloP100

0.14

PrimateAI

Benign

0.46

PROVEAN

Benign

0.78

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.058

MutPred

0.20

Loss of MoRF binding (P = 0.0817);

MPC

0.084

ClinPred

0.0017

GERP RS

4.1

Varity_R

0.11

gMVP

0.17

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over