Genetic Variant RAB40A:p.Ser216Ile (chrX-103500110-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_080879.3(RAB40A):c.647G>T(p.Ser216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,209,585 control chromosomes in the GnomAD database, including 1 homozygotes. There are 356 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00060 ( 1 hom. 347 hem. )

Consequence

RAB40A
NM_080879.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.23

Variant links:

Genes affected

RAB40A (HGNC:18283): (RAB40A, member RAS oncogene family) This gene encodes a member of the Rab40 subfamily of Rab small GTP-binding proteins that contains a C-terminal suppressors of cytokine signaling box. [provided by RefSeq, Apr 2010]

RAB40A links:

ENSG00000234405 (HGNC:):

ENSG00000234405 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05337599).

BP6

Variant X-103500110-C-A is Benign according to our data. Variant chrX-103500110-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2332633.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-103500110-C-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB40A	NM_080879.3 link	c.647G>T	p.Ser216Ile	missense_variant	Exon 3 of 3	ENST00000304236.2	NP_543155.2	Q8WXH6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB40A	ENST00000304236.2 link	c.647G>T	p.Ser216Ile	missense_variant	Exon 3 of 3	2	NM_080879.3	ENSP00000305648.1		Q8WXH6

Frequencies

GnomAD3 genomes

AF:

0.000445

AC:

AN:

112479

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

34637

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000732

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

183475

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

67913

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000216

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000598

AC:

656

AN:

1097050

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

347

AN XY:

363514

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000298

Gnomad4 SAS exome

AF:

0.000536

Gnomad4 FIN exome

AF:

0.000321

Gnomad4 NFE exome

AF:

0.000671

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000444

AC:

AN:

112535

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

AN XY:

34701

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000162

Gnomad4 NFE

AF:

0.000732

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000790

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 22, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.090

DANN

Benign

0.39

DEOGEN2

Benign

0.0020

T;T

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.050

.;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

0.44

N;N

REVEL

Benign

0.11

Sift

Benign

0.38

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;B

Vest4

0.067

MVP

0.58

MPC

0.94

ClinPred

0.013

GERP RS

-0.45

Varity_R

0.051

gMVP

0.087

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.

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