Genetic Variant RAB3IL1:p.Ala270Thr (chr11-61904637-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_013401.4(RAB3IL1):c.808G>A(p.Ala270Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,611,732 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RAB3IL1
NM_013401.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.00

Variant links:

Genes affected

RAB3IL1 (HGNC:9780): (RAB3A interacting protein like 1) This gene encodes a guanine nucleotide exchange factor for the ras-related protein Rab3A. The encoded protein binds Rab3a and the inositol hexakisphosphate kinase InsP6K1. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Nov 2012]

RAB3IL1 links:

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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, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB3IL1	NM_013401.4 link	c.808G>A	p.Ala270Thr	missense_variant	Exon 7 of 10	ENST00000394836.7	NP_037533.2	Q8TBN0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAB3IL1	ENST00000394836.7 link	c.808G>A	p.Ala270Thr	missense_variant	Exon 7 of 10	1	NM_013401.4	ENSP00000378313.2	Q8TBN0-1
RAB3IL1	ENST00000301773.9 link	c.730G>A	p.Ala244Thr	missense_variant	Exon 6 of 9	1		ENSP00000301773.5	Q8TBN0-2
RAB3IL1	ENST00000531922.2 link	c.1093G>A	p.Ala365Thr	missense_variant	Exon 8 of 11	3		ENSP00000435444.2	E9PK89
RAB3IL1	ENST00000530888.1 link	n.66G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152194

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245700

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133234

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:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459538

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

725858

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

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:

0.0000735

Gnomad4 OTH

AF:

0.00

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

Nov 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.808G>A (p.A270T) alteration is located in exon 7 (coding exon 7) of the RAB3IL1 gene. This alteration results from a G to A substitution at nucleotide position 808, causing the alanine (A) at amino acid position 270 to be replaced by a threonine (T). 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

0.58

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.62

Gain of phosphorylation at A270 (P = 0.0728);.;

MVP

0.79

MPC

0.44

ClinPred

0.97

GERP RS

4.9

Varity_R

0.45

gMVP

0.70

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