Genetic Variant ARHGEF39:p.Ala27Ser (chr9-35665091-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_032818.3(ARHGEF39):c.79G>T(p.Ala27Ser) 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. 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. A27V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF39
NM_032818.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

Variant links:

Genes affected

ARHGEF39 (HGNC:25909): (Rho guanine nucleotide exchange factor 39) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell migration. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF39 links:

ENSG00000303835 (HGNC:):

ENSG00000303835 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4056918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF39	NM_032818.3 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 9	ENST00000378387.4	NP_116207.2	Q8N4T4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF39	ENST00000378387.4 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 1 of 9	1	NM_032818.3	ENSP00000367638.3		Q8N4T4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

154498

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1400474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691068

African (AFR)

AF:

0.00

AC:

AN:

32324

American (AMR)

AF:

0.00

AC:

AN:

35866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

36728

South Asian (SAS)

AF:

0.00

AC:

AN:

79710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081380

Other (OTH)

AF:

0.00

AC:

AN:

58048

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000877

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.79G>T (p.A27S) alteration is located in exon 1 (coding exon 1) of the ARHGEF39 gene. This alteration results from a G to T substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 to be replaced by a serine (S). 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

0.14

BayesDel_addAF

Benign

0.0081

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.28

MutationAssessor

Uncertain

2.2

PhyloP100

2.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

REVEL

Benign

0.27

Sift

Benign

0.088

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.33

MutPred

0.64

Gain of phosphorylation at A27 (P = 0.0323);

MVP

0.50

MPC

0.79

ClinPred

0.99

GERP RS

5.3

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.16

gMVP

0.40

Mutation Taster

=77/23

polymorphism

(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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over