Variant chr4-26735457-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018317.4(TBC1D19):c.1087G>A(p.Val363Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,529,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

TBC1D19
NM_018317.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.08

Variant links:

Genes affected

TBC1D19 (HGNC:25624): (TBC1 domain family member 19) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D19 links:

TBC1D19 (HGNC:):

TBC1D19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3621703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D19	NM_018317.4 linkuse as main transcript	c.1087G>A	p.Val363Ile	missense_variant, splice_region_variant	16/21	ENST00000264866.9	NP_060787.2	Q8N5T2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TBC1D19	ENST00000264866.9 linkuse as main transcript	c.1087G>A	p.Val363Ile	missense_variant, splice_region_variant	16/21	1	NM_018317.4	ENSP00000264866.4	Q8N5T2-1
TBC1D19	ENST00000511789.5 linkuse as main transcript	c.892G>A	p.Val298Ile	missense_variant, splice_region_variant	13/18	1		ENSP00000425569.1	Q8N5T2-2
TBC1D19	ENST00000502873.5 linkuse as main transcript	n.1197G>A		splice_region_variant, non_coding_transcript_exon_variant	16/20	1

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

146002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000252

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:

0.0000451

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000445

AC:

AN:

179600

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

96328

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000526

Gnomad NFE exome

AF:

0.0000661

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000484

AC:

AN:

1383264

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

685508

show subpopulations

Gnomad4 AFR exome

AF:

0.0000332

Gnomad4 AMR exome

AF:

0.0000286

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.0000581

Gnomad4 OTH exome

AF:

0.0000352

GnomAD4 genome

AF:

0.0000274

AC:

AN:

146002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70700

show subpopulations

Gnomad4 AFR

AF:

0.0000252

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:

0.0000451

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000948

Hom.:

ExAC

AF:

0.0000251

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The c.1087G>A (p.V363I) alteration is located in exon 16 (coding exon 16) of the TBC1D19 gene. This alteration results from a G to A substitution at nucleotide position 1087, causing the valine (V) at amino acid position 363 to be replaced by an isoleucine (I). 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

0.091

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.15

Sift

Benign

0.16

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.84

P;.

Vest4

0.63

MutPred

0.45

Loss of catalytic residue at V363 (P = 0.0062);.;

MVP

0.44

MPC

0.32

ClinPred

0.12

GERP RS

5.7

Varity_R

0.14

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -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