Genetic Variant TBC1D19:p.Arg122Gln (chr4-26637281-G-A) – 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.365G>A(p.Arg122Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,607,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

TBC1D19
NM_018317.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75

Publications

3 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=0.08246222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4 link	c.365G>A	p.Arg122Gln	missense_variant	Exon 5 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.365G>A	p.Arg122Gln	missense_variant	Exon 5 of 21	1	NM_018317.4	ENSP00000264866.4		Q8N5T2-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

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

GnomAD2 exomes

AF:

0.0000488

AC:

AN:

245740

AF XY:

0.0000301

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000406

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000714

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1454942

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

723784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33100

American (AMR)

AF:

0.00

AC:

AN:

43844

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39356

South Asian (SAS)

AF:

0.00

AC:

AN:

84922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1108744

Other (OTH)

AF:

0.0000999

AC:

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.365G>A (p.R122Q) alteration is located in exon 5 (coding exon 5) of the TBC1D19 gene. This alteration results from a G to A substitution at nucleotide position 365, causing the arginine (R) at amino acid position 122 to be replaced by a glutamine (Q). 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

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.040

.;T;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.041

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Benign

0.0098

MetaRNN

Benign

0.082

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

.;L;.;.;.

PhyloP100

2.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.055

Sift

Benign

0.26

T;T;T;T;T

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.0040

.;B;.;.;.

Vest4

0.13, 0.11

MVP

0.52

MPC

0.34

ClinPred

0.15

GERP RS

4.2

Varity_R

0.089

gMVP

0.40

Mutation Taster

=87/13

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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4-26637281-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over