Variant 2-38953238-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001145451.5(ARHGEF33):c.1130T>C(p.Leu377Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000243 in 1,521,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ARHGEF33
NM_001145451.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.36

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:

LOC105374471 (HGNC:):

LOC105374471 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33534765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF33	NM_001145451.5 linkuse as main transcript	c.1130T>C	p.Leu377Pro	missense_variant	12/18	ENST00000409978.7
LOC105374471	XR_939980.3 linkuse as main transcript	n.46+168A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF33	ENST00000409978.7 linkuse as main transcript	c.1130T>C	p.Leu377Pro	missense_variant	12/18	5	NM_001145451.5	P1	A8MVX0-2
ARHGEF33	ENST00000698009.1 linkuse as main transcript	c.1274T>C	p.Leu425Pro	missense_variant	13/19
ARHGEF33	ENST00000398800.8 linkuse as main transcript	c.1130T>C	p.Leu377Pro	missense_variant	10/16	5		P1	A8MVX0-2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000506

AC:

AN:

158208

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

83410

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1369374

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

677384

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.51e-7

Gnomad4 OTH exome

AF:

0.0000526

GnomAD4 genome

AF:

0.000118

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000434

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000390

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

Dec 22, 2023

The c.1130T>C (p.L377P) alteration is located in exon 10 (coding exon 10) of the ARHGEF33 gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the leucine (L) at amino acid position 377 to be replaced by a proline (P). 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

0.013

BayesDel_noAF

Pathogenic

0.14

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.042

D;D

Vest4

0.78

MVP

0.62

ClinPred

0.10

GERP RS

5.4

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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