Genetic Variant TBC1D19:p.Leu176Val (chr4-26659642-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018317.4(TBC1D19):c.526C>G(p.Leu176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L176F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TBC1D19
NM_018317.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12006706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4 link	c.526C>G	p.Leu176Val	missense_variant	Exon 8 of 21	ENST00000264866.9	NP_060787.2	Q8N5T2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D19	ENST00000264866.9 link	c.526C>G	p.Leu176Val	missense_variant	Exon 8 of 21	1	NM_018317.4	ENSP00000264866.4		Q8N5T2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1441344

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25482

East Asian (EAS)

AF:

0.00

AC:

AN:

39342

South Asian (SAS)

AF:

0.00

AC:

AN:

83170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1097802

Other (OTH)

AF:

0.00

AC:

AN:

59430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.526C>G (p.L176V) alteration is located in exon 8 (coding exon 8) of the TBC1D19 gene. This alteration results from a C to G substitution at nucleotide position 526, causing the leucine (L) at amino acid position 176 to be replaced by a valine (V). 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

0.065

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.011

.;T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.0043

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.40

.;N;.;.

PhyloP100

1.7

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.42

N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.55

T;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.13, 0.15

MutPred

0.25

.;Gain of sheet (P = 0.0266);.;.;

MVP

0.34

MPC

0.30

ClinPred

0.29

GERP RS

5.3

Varity_R

0.12

gMVP

0.18

Mutation Taster

=77/23

polymorphism

(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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4-26659642-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over