Genetic Variant NM_001001669.3:c.176G>T (chr5-149597945-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001001669.3(ARHGEF37):c.176G>T(p.Arg59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF37
NM_001001669.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22253191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF37	NM_001001669.3 link	c.176G>T	p.Arg59Leu	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>T	p.Arg59Leu	missense_variant	Exon 2 of 13	2	NM_001001669.3	ENSP00000328083.6		A1IGU5
ARHGEF37	ENST00000505810.5 link	c.176G>T	p.Arg59Leu	missense_variant	Exon 2 of 3	5		ENSP00000425621.1		D6RJH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1436348

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712916

African (AFR)

AF:

0.00

AC:

AN:

32530

American (AMR)

AF:

0.00

AC:

AN:

40308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25548

East Asian (EAS)

AF:

0.00

AC:

AN:

38142

South Asian (SAS)

AF:

0.00

AC:

AN:

81982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100468

Other (OTH)

AF:

0.00

AC:

AN:

59490

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.176G>T (p.R59L) alteration is located in exon 2 (coding exon 1) of the ARHGEF37 gene. This alteration results from a G to T substitution at nucleotide position 176, causing the arginine (R) at amino acid position 59 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0072

.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

.;L

PhyloP100

0.034

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.13

Sift

Benign

0.073

T;T

Sift4G

Uncertain

0.060

T;T

Polyphen

0.34

.;B

Vest4

0.30

MutPred

0.72

Loss of disorder (P = 0.0604);Loss of disorder (P = 0.0604);

MVP

0.28

MPC

0.23

ClinPred

0.45

GERP RS

-0.045

Varity_R

0.13

gMVP

0.25

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over