Genetic Variant NM_080879.3:c.163A>G (chrX-103500594-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_080879.3(RAB40A):c.163A>G(p.Thr55Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000061 in 1,098,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000061 ( 0 hom. 20 hem. )

Failed GnomAD Quality Control

Consequence

RAB40A
NM_080879.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

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:

LL0XNC01-250H12.3 (HGNC:):

LL0XNC01-250H12.3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3989887).

BS2

High Hemizygotes in GnomAdExome4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB40A	NM_080879.3 link	c.163A>G	p.Thr55Ala	missense_variant	Exon 3 of 3	ENST00000304236.2	NP_543155.2	Q8WXH6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB40A	ENST00000304236.2 link	c.163A>G	p.Thr55Ala	missense_variant	Exon 3 of 3	2	NM_080879.3	ENSP00000305648.1	Q8WXH6
RAB40A	ENST00000372633.1 link	c.163A>G	p.Thr55Ala	missense_variant	Exon 1 of 1	6		ENSP00000361716.1	Q8WXH6
ENSG00000234405	ENST00000658164.1 link	n.999+2981T>C		intron_variant	Intron 2 of 2
ENSG00000234405	ENST00000667819.1 link	n.302+2981T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000905

AC:

AN:

110557

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32787

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

183508

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67936

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1098220

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

363592

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:

0.0000784

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000905

AC:

AN:

110557

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32787

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:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163A>G (p.T55A) alteration is located in exon 3 (coding exon 1) of the RAB40A gene. This alteration results from a A to G substitution at nucleotide position 163, causing the threonine (T) at amino acid position 55 to be replaced by an alanine (A). 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

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Benign

0.0039

MetaRNN

Benign

0.40

T;T

MetaSVM

Uncertain

-0.053

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.049

D;D

Polyphen

1.0

D;D

Vest4

0.23

MutPred

0.64

Gain of ubiquitination at K52 (P = 0.102);Gain of ubiquitination at K52 (P = 0.102);

MVP

0.97

MPC

1.8

ClinPred

0.92

GERP RS

0.85

Varity_R

0.46

gMVP

0.68

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