chrX-70283356-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001363807.1(RAB41):ā€‹c.326T>Cā€‹(p.Val109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000166 in 1,202,040 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000089 ( 0 hom., 1 hem., cov: 23)
Exomes š‘“: 0.000017 ( 0 hom. 4 hem. )

Consequence

RAB41
NM_001363807.1 missense

Scores

3
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.35
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.747
BS2
High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAB41NM_001363807.1 linkuse as main transcriptc.326T>C p.Val109Ala missense_variant 4/8 ENST00000374473.6 NP_001350736.1
RAB41NM_001032726.3 linkuse as main transcriptc.323T>C p.Val108Ala missense_variant 4/8 NP_001027898.2 Q5JT25-2
RAB41XM_011530948.4 linkuse as main transcriptc.326T>C p.Val109Ala missense_variant 4/7 XP_011529250.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAB41ENST00000374473.6 linkuse as main transcriptc.326T>C p.Val109Ala missense_variant 4/85 NM_001363807.1 ENSP00000363597.2 Q5JT25-1
RAB41ENST00000276066.4 linkuse as main transcriptc.323T>C p.Val108Ala missense_variant 4/81 ENSP00000276066.4 Q5JT25-2
PDZD11ENST00000695560.1 linkuse as main transcriptn.*97-1081A>G intron_variant ENSP00000512017.1 Q5EBL8-1

Frequencies

GnomAD3 genomes
AF:
0.00000890
AC:
1
AN:
112360
Hom.:
0
Cov.:
23
AF XY:
0.0000290
AC XY:
1
AN XY:
34508
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000174
AC:
19
AN:
1089680
Hom.:
0
Cov.:
29
AF XY:
0.0000113
AC XY:
4
AN XY:
355226
show subpopulations
Gnomad4 AFR exome
AF:
0.0000381
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:
0.0000192
Gnomad4 OTH exome
AF:
0.0000436
GnomAD4 genome
AF:
0.00000890
AC:
1
AN:
112360
Hom.:
0
Cov.:
23
AF XY:
0.0000290
AC XY:
1
AN XY:
34508
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 submitterclinical testingAmbry GeneticsDec 03, 2024The c.323T>C (p.V108A) alteration is located in exon 4 (coding exon 4) of the RAB41 gene. This alteration results from a T to C substitution at nucleotide position 323, causing the valine (V) at amino acid position 108 to be replaced by an alanine (A). 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
0.72
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D;.
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.022
T
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
1.7
L;.
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Uncertain
0.48
Sift
Uncertain
0.026
D;D
Sift4G
Uncertain
0.019
D;D
Polyphen
1.0
D;D
Vest4
0.61
MutPred
0.60
Gain of catalytic residue at V109 (P = 0.1708);.;
MVP
1.0
MPC
0.70
ClinPred
0.98
D
GERP RS
1.2
Varity_R
0.32
gMVP
0.68

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.

Other links and lift over

dbSNP: rs1404416454; hg19: chrX-69503206; API