Genetic Variant RAB40C:p.Leu175Phe (chr16-626079-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_021168.5(RAB40C):c.523C>T(p.Leu175Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RAB40C
NM_021168.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00

Variant links:

Genes affected

RAB40C (HGNC:18285): (RAB40C, member RAS oncogene family) Predicted to enable GDP binding activity; GTP binding activity; and GTPase activity. Predicted to be involved in protein localization to plasma membrane. Predicted to be located in perinuclear region of cytoplasm. Predicted to be active in endosome; plasma membrane; and synaptic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

RAB40C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB40C	NM_021168.5 link	c.523C>T	p.Leu175Phe	missense_variant	Exon 5 of 6	ENST00000248139.8	NP_066991.3	Q96S21-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB40C	ENST00000248139.8 link	c.523C>T	p.Leu175Phe	missense_variant	Exon 5 of 6	1	NM_021168.5	ENSP00000248139.3		Q96S21-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251032

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135836

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460934

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726808

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523C>T (p.L175F) alteration is located in exon 6 (coding exon 5) of the RAB40C gene. This alteration results from a C to T substitution at nucleotide position 523, causing the leucine (L) at amino acid position 175 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

0.93

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;D;.;D;D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

.;D;.;D;D;.;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.6

L;.;L;.;L;L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

D;D;D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;D;D;.

Vest4

0.83

MutPred

0.62

Gain of MoRF binding (P = 0.1197);Gain of MoRF binding (P = 0.1197);Gain of MoRF binding (P = 0.1197);Gain of MoRF binding (P = 0.1197);Gain of MoRF binding (P = 0.1197);Gain of MoRF binding (P = 0.1197);.;

MVP

0.94

MPC

2.2

ClinPred

0.98

GERP RS

5.2

Varity_R

0.55

gMVP

0.84

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