Variant 2-38931191-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145451.5(ARHGEF33):c.445G>A(p.Glu149Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ARHGEF33
NM_001145451.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF33	NM_001145451.5 link	c.445G>A	p.Glu149Lys	missense_variant	7/18	ENST00000409978.7	NP_001138923.2	A8MVX0-2
ARHGEF33	NM_001367623.3 link	c.445G>A	p.Glu149Lys	missense_variant	7/19		NP_001354552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARHGEF33	ENST00000409978.7 link	c.445G>A	p.Glu149Lys	missense_variant	7/18	5	NM_001145451.5	ENSP00000387020.1	A8MVX0-2
ARHGEF33	ENST00000698009.1 link	c.589G>A	p.Glu197Lys	missense_variant	8/19			ENSP00000513494.1	A0A8V8TLC5
ARHGEF33	ENST00000398800.8 link	c.445G>A	p.Glu149Lys	missense_variant	5/16	5		ENSP00000381780.4	A8MVX0-2
ARHGEF33	ENST00000488692.1 link	n.497G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Sep 11, 2024

The c.445G>A (p.E149K) alteration is located in exon 5 (coding exon 5) of the ARHGEF33 gene. This alteration results from a G to A substitution at nucleotide position 445, causing the glutamic acid (E) at amino acid position 149 to be replaced by a lysine (K). 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

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.81

L;L

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.023

D;D

Vest4

0.82

MutPred

0.22

Gain of ubiquitination at E149 (P = 0.0031);Gain of ubiquitination at E149 (P = 0.0031);

MVP

0.33

ClinPred

0.96

GERP RS

5.7

gMVP

0.46

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