Variant chr2-38931133-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145451.5(ARHGEF33):c.387C>G(p.Ser129Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000503 in 1,550,368 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ARHGEF33
NM_001145451.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0310

Variant links:

Genes affected

ARHGEF33 (HGNC:37252): (Rho guanine nucleotide exchange factor 33) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF33 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0036302805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5 linkuse as main transcript	c.387C>G	p.Ser129Arg	missense_variant	7/18	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3 linkuse as main transcript	c.387C>G	p.Ser129Arg	missense_variant	7/19		NP_001354552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF33	ENST00000409978.7 linkuse as main transcript	c.387C>G	p.Ser129Arg	missense_variant	7/18	5	NM_001145451.5	ENSP00000387020	P1	A8MVX0-2
ARHGEF33	ENST00000698009.1 linkuse as main transcript	c.531C>G	p.Ser177Arg	missense_variant	8/19			ENSP00000513494
ARHGEF33	ENST00000398800.8 linkuse as main transcript	c.387C>G	p.Ser129Arg	missense_variant	5/16	5		ENSP00000381780	P1	A8MVX0-2
ARHGEF33	ENST00000488692.1 linkuse as main transcript	n.439C>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000451

AC:

AN:

155068

Hom.:

AF XY:

0.0000365

AC XY:

AN XY:

82122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000460

GnomAD4 exome

AF:

0.0000222

AC:

AN:

1398036

Hom.:

Cov.:

AF XY:

0.00000870

AC XY:

AN XY:

689560

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000510

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000224

GnomAD4 genome

AF:

0.000309

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.000744

ExAC

AF:

0.0000399

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.387C>G (p.S129R) alteration is located in exon 5 (coding exon 5) of the ARHGEF33 gene. This alteration results from a C to G substitution at nucleotide position 387, causing the serine (S) at amino acid position 129 to be replaced by an arginine (R). 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

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.79

.;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.16

Sift

Benign

0.070

T;T

Sift4G

Benign

0.30

T;T

Vest4

0.28

MutPred

0.099

Loss of phosphorylation at S129 (P = 0.0121);Loss of phosphorylation at S129 (P = 0.0121);

MVP

0.030

ClinPred

0.045

GERP RS

-3.3

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over