X-70283371-C-T

Position:

chrX-70283371-C-T

Variant summary

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

The NM_001363807.1(RAB41):c.341C>T(p.Thr114Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,185,428 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00013 ( 0 hom. 37 hem. )

Consequence

RAB41
NM_001363807.1 missense, splice_region

Scores

Splicing: ADA: 0.9334

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

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 Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB41	NM_001363807.1 linkuse as main transcript	c.341C>T	p.Thr114Ile	missense_variant, splice_region_variant	4/8	ENST00000374473.6	NP_001350736.1
RAB41	NM_001032726.3 linkuse as main transcript	c.338C>T	p.Thr113Ile	missense_variant, splice_region_variant	4/8		NP_001027898.2	Q5JT25-2
RAB41	XM_011530948.4 linkuse as main transcript	c.341C>T	p.Thr114Ile	missense_variant, splice_region_variant	4/7		XP_011529250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RAB41	ENST00000374473.6 linkuse as main transcript	c.341C>T	p.Thr114Ile	missense_variant, splice_region_variant	4/8	5	NM_001363807.1	ENSP00000363597.2	Q5JT25-1
RAB41	ENST00000276066.4 linkuse as main transcript	c.338C>T	p.Thr113Ile	missense_variant, splice_region_variant	4/8	1		ENSP00000276066.4	Q5JT25-2
PDZD11	ENST00000695560.1 linkuse as main transcript	n.*97-1096G>A		intron_variant				ENSP00000512017.1	Q5EBL8-1

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

112045

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34237

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:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000711

AC:

AN:

182839

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

67299

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.000135

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000130

AC:

140

AN:

1073383

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

340127

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:

0.000167

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000714

AC:

AN:

112045

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34237

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:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

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 04, 2024

The c.338C>T (p.T113I) alteration is located in exon 4 (coding exon 4) of the RAB41 gene. This alteration results from a C to T substitution at nucleotide position 338, causing the threonine (T) at amino acid position 113 to be replaced by an isoleucine (I). 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

0.96

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Uncertain

0.080

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.55

MVP

0.99

MPC

0.52

ClinPred

0.68

GERP RS

-0.57

Varity_R

0.45

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.62

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.36

Position offset: 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