X-70282339-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001363807.1(RAB41):c.122G>A(p.Ser41Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,210,146 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 5 hem. )

Consequence

RAB41
NM_001363807.1 missense, splice_region

Scores

Splicing: ADA: 0.0003483

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24922249).

BS2

High Hemizygotes in GnomAdExome at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RAB41	NM_001363807.1 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/8	ENST00000374473.6
RAB41	NM_001032726.3 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/8
RAB41	XM_011530948.4 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB41	ENST00000374473.6 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/8	5	NM_001363807.1	P1	Q5JT25-1
RAB41	ENST00000276066.4 linkuse as main transcript	c.122G>A	p.Ser41Asn	missense_variant, splice_region_variant	1/8	1			Q5JT25-2
RAB41	ENST00000509895.5 linkuse as main transcript	c.-223G>A		5_prime_UTR_variant	1/3	4
PDZD11	ENST00000695560.1 linkuse as main transcript	c.*97-64C>T		intron_variant, NMD_transcript_variant					Q5EBL8-1

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112048

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34214

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000564

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:

0.0000218

AC:

AN:

183321

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

67757

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:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1098044

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

0.00000831

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000535

AC:

AN:

112102

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000564

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:

0.000136

ExAC

AF:

0.0000165

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

Feb 13, 2024

The c.122G>A (p.S41N) alteration is located in exon 1 (coding exon 1) of the RAB41 gene. This alteration results from a G to A substitution at nucleotide position 122, causing the serine (S) at amino acid position 41 to be replaced by an asparagine (N). 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

Benign

0.31

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Uncertain

0.54

D;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

D;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.044

D;D

Polyphen

0.96

P;P

Vest4

0.23

MutPred

0.57

Gain of ubiquitination at K44 (P = 0.0725);Gain of ubiquitination at K44 (P = 0.0725);

MVP

0.66

MPC

0.18

ClinPred

0.18

GERP RS

2.3

Varity_R

0.32

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00035

dbscSNV1_RF

Benign

0.028

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.

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