Genetic Variant RAB3D:p.Arg178Ser (chr19-11325526-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004283.4(RAB3D):c.532C>A(p.Arg178Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R178C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RAB3D
NM_004283.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.81

Publications

3 publications found

Variant links:

Genes affected

RAB3D (HGNC:9779): (RAB3D, member RAS oncogene family) Enables myosin V binding activity. Involved in bone resorption and positive regulation of regulated secretory pathway. Located in cytoplasmic microtubule and secretory vesicle. [provided by Alliance of Genome Resources, Apr 2022]

RAB3D links:

TSPAN16 (HGNC:30725): (tetraspanin 16) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein might couple to signal transduction pathways and possibly modulate cellular activation and adhesion in haemopoietic and neural tissue. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

TSPAN16 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3D	NM_004283.4 link	c.532C>A	p.Arg178Ser	missense_variant	Exon 5 of 5	ENST00000222120.8	NP_004274.1	O95716A0A024R7G2
TSPAN16	NM_012466.4 link	c.688-1268G>T		intron_variant	Intron 6 of 6		NP_036598.1	Q9UKR8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB3D	ENST00000222120.8 link	c.532C>A	p.Arg178Ser	missense_variant	Exon 5 of 5	1	NM_004283.4	ENSP00000222120.2	O95716
TSPAN16	ENST00000316737.5 link	c.688-1268G>T		intron_variant	Intron 6 of 6	1		ENSP00000319486.1	Q9UKR8-1
RAB3D	ENST00000589655.1 link	c.532C>A	p.Arg178Ser	missense_variant	Exon 5 of 5	2		ENSP00000466000.1	O95716

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251076

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461374

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000195

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.039

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.31

N;N

PhyloP100

5.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.78

N;.

REVEL

Uncertain

0.36

Sift

Benign

0.59

T;.

Sift4G

Benign

0.54

T;T

Polyphen

0.14

B;B

Vest4

0.62

MutPred

0.55

Loss of stability (P = 0.0465);Loss of stability (P = 0.0465);

MVP

0.81

MPC

0.62

ClinPred

0.45

GERP RS

3.7

Varity_R

0.48

gMVP

0.71

Mutation Taster

=32/68

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over