Variant 2-38929743-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001145451.5(ARHGEF33):c.275C>A(p.Ala92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,551,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ARHGEF33
NM_001145451.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06911737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5 linkuse as main transcript	c.275C>A	p.Ala92Asp	missense_variant	6/18	ENST00000409978.7	NP_001138923.2
ARHGEF33	NM_001367623.3 linkuse as main transcript	c.275C>A	p.Ala92Asp	missense_variant	6/19		NP_001354552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF33	ENST00000409978.7 linkuse as main transcript	c.275C>A	p.Ala92Asp	missense_variant	6/18	5	NM_001145451.5	ENSP00000387020	P1	A8MVX0-2
ARHGEF33	ENST00000698009.1 linkuse as main transcript	c.419C>A	p.Ala140Asp	missense_variant	7/19			ENSP00000513494
ARHGEF33	ENST00000398800.8 linkuse as main transcript	c.275C>A	p.Ala92Asp	missense_variant	4/16	5		ENSP00000381780	P1	A8MVX0-2
ARHGEF33	ENST00000488692.1 linkuse as main transcript	n.327C>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000696

AC:

AN:

157950

Hom.:

AF XY:

0.0000841

AC XY:

AN XY:

83248

show subpopulations

Gnomad AFR exome

AF:

0.000121

Gnomad AMR exome

AF:

0.00

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:

0.000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

373

AN:

1399466

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

168

AN XY:

690206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000950

Gnomad4 AMR exome

AF:

0.00

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:

0.000338

Gnomad4 OTH exome

AF:

0.0000860

GnomAD4 genome

AF:

0.000118

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000276

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00126

AC:

ExAC

AF:

0.000118

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

Apr 20, 2023

The c.275C>A (p.A92D) alteration is located in exon 4 (coding exon 4) of the ARHGEF33 gene. This alteration results from a C to A substitution at nucleotide position 275, causing the alanine (A) at amino acid position 92 to be replaced by an aspartic acid (D). 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

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

0.094

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.90

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.10

Sift

Benign

0.46

T;T

Sift4G

Benign

0.50

T;T

Vest4

0.25

MVP

0.34

ClinPred

0.071

GERP RS

5.5

gMVP

0.48

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