Genetic Variant NM_001001669.3:c.1261A>C (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

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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