X-70284271-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001363807.1(RAB41):c.555C>G(p.Phe185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000333 in 1,201,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

RAB41
NM_001363807.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.723

Variant links:

Genes affected

RAB41 (HGNC:18293): (RAB41, member RAS oncogene family) This gene encodes a small GTP-binding protein that belongs to the largest family within the Ras superfamily. These proteins function as regulators of membrane trafficking. They cycle between inactive GDP-bound and activated GTP-bound states, which is controlled by GTP hydrolysis-activating proteins (GAPs). This family member can be activated by the GAP protein RN-Tre, and it is localized to the Golgi complex. [provided by RefSeq, May 2010]

RAB41 links:

PDZD11 (HGNC:28034): (PDZ domain containing 11) Enables protein C-terminus binding activity. Involved in pore complex assembly. Located in basolateral plasma membrane and cytosol. Part of pore complex. [provided by Alliance of Genome Resources, Apr 2022]

PDZD11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB41	NM_001363807.1 link	c.555C>G	p.Phe185Leu	missense_variant	Exon 7 of 8	ENST00000374473.6	NP_001350736.1
RAB41	NM_001032726.3 link	c.552C>G	p.Phe184Leu	missense_variant	Exon 7 of 8		NP_001027898.2	Q5JT25-2
RAB41	XM_011530948.4 link	c.555C>G	p.Phe185Leu	missense_variant	Exon 7 of 7		XP_011529250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB41	ENST00000374473.6 link	c.555C>G	p.Phe185Leu	missense_variant	Exon 7 of 8	5	NM_001363807.1	ENSP00000363597.2	Q5JT25-1
RAB41	ENST00000276066.4 link	c.552C>G	p.Phe184Leu	missense_variant	Exon 7 of 8	1		ENSP00000276066.4	Q5JT25-2
PDZD11	ENST00000695561.1 link	n.3655G>C		non_coding_transcript_exon_variant	Exon 6 of 6
PDZD11	ENST00000695560.1 link	n.*97-1996G>C		intron_variant	Intron 7 of 7			ENSP00000512017.1	Q5EBL8-1

Frequencies

GnomAD3 genomes

AF:

0.0000286

AC:

AN:

105045

Hom.:

Cov.:

AF XY:

0.0000356

AC XY:

AN XY:

28125

show subpopulations

Gnomad AFR

AF:

0.000105

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

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000286

AC:

AN:

105045

Hom.:

Cov.:

AF XY:

0.0000356

AC XY:

AN XY:

28125

show subpopulations

Gnomad4 AFR

AF:

0.000105

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

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.552C>G (p.F184L) alteration is located in exon 7 (coding exon 7) of the RAB41 gene. This alteration results from a C to G substitution at nucleotide position 552, causing the phenylalanine (F) at amino acid position 184 to be replaced by a leucine (L). 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.61

D;.

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.45

MutPred

0.89

Loss of methylation at K183 (P = 0.0887);.;

MVP

0.87

MPC

0.65

ClinPred

1.0

GERP RS

-1.4

Varity_R

0.39

gMVP

0.91

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