X-70283331-A-T

Position:

chrX-70283331-A-T

Variant summary

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

The NM_001363807.1(RAB41):c.301A>T(p.Ile101Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,209,405 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000036 ( 0 hom. 15 hem. )

Consequence

RAB41
NM_001363807.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

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, 0.747

BS2

High Hemizygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB41	NM_001363807.1 linkuse as main transcript	c.301A>T	p.Ile101Phe	missense_variant	4/8	ENST00000374473.6	NP_001350736.1
RAB41	NM_001032726.3 linkuse as main transcript	c.298A>T	p.Ile100Phe	missense_variant	4/8		NP_001027898.2	Q5JT25-2
RAB41	XM_011530948.4 linkuse as main transcript	c.301A>T	p.Ile101Phe	missense_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.301A>T	p.Ile101Phe	missense_variant	4/8	5	NM_001363807.1	ENSP00000363597.2	Q5JT25-1
RAB41	ENST00000276066.4 linkuse as main transcript	c.298A>T	p.Ile100Phe	missense_variant	4/8	1		ENSP00000276066.4	Q5JT25-2
PDZD11	ENST00000695560.1 linkuse as main transcript	n.*97-1056T>A		intron_variant				ENSP00000512017.1	Q5EBL8-1
RAB41	ENST00000509895.5 linkuse as main transcript	c.*44A>T		downstream_gene_variant		4		ENSP00000421643.1	D6REW8

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112461

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34619

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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

GnomAD3 exomes

AF:

0.0000600

AC:

AN:

183393

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67829

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

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:

0.0000977

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1096944

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

362306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000392

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112461

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34619

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Oct 04, 2024

The c.298A>T (p.I100F) alteration is located in exon 4 (coding exon 4) of the RAB41 gene. This alteration results from a A to T substitution at nucleotide position 298, causing the isoleucine (I) at amino acid position 100 to be replaced by a phenylalanine (F). 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

0.59

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.88

L;.

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.076

T;D

Polyphen

1.0

D;D

Vest4

0.56

MutPred

0.59

Loss of catalytic residue at I101 (P = 0.0652);.;

MVP

0.94

MPC

0.82

ClinPred

0.70

GERP RS

-1.1

Varity_R

0.82

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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