Genetic Variant RAB41:p.Glu214Lys (chrX-70284614-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001363807.1(RAB41):c.640G>A(p.Glu214Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,874 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E214Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

RAB41
NM_001363807.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.265

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05971718).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363807.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB41	NM_001363807.1	MANE Select	c.640G>A	p.Glu214Lys	missense	Exon 8 of 8	NP_001350736.1	Q5JT25-1
	RAB41	NM_001032726.3		c.637G>A	p.Glu213Lys	missense	Exon 8 of 8	NP_001027898.2	Q5JT25-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAB41	ENST00000374473.6	TSL:5 MANE Select	c.640G>A	p.Glu214Lys	missense	Exon 8 of 8	ENSP00000363597.2	Q5JT25-1
RAB41	ENST00000276066.4	TSL:1	c.637G>A	p.Glu213Lys	missense	Exon 8 of 8	ENSP00000276066.4	Q5JT25-2
PDZD11	ENST00000695561.1		n.3312C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183422

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1095874

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26349

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54085

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839985

Other (OTH)

AF:

0.0000217

AC:

AN:

46016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.32

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.019

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.53

M_CAP

Benign

0.013

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.27

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.69

REVEL

Benign

0.041

Sift

Benign

0.18

Sift4G

Benign

0.38

Polyphen

0.0050

Vest4

0.072

MutPred

0.26

Gain of ubiquitination at E214 (P = 0.0022)

MVP

0.57

MPC

0.17

ClinPred

0.072

GERP RS

-4.8

Varity_R

0.060

gMVP

0.67

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over