chr4-26673836-C-A

Variant names:

• chr4-26673836-C-A
• NM_018317.4:c.764C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018317.4(TBC1D19):​c.764C>A​(p.Ala255Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBC1D19 NM_018317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26428372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4	c.764C>A	p.Ala255Glu	missense_variant	Exon 11 of 21	ENST00000264866.9	NP_060787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D19	ENST00000264866.9	c.764C>A	p.Ala255Glu	missense_variant	Exon 11 of 21	1	NM_018317.4	ENSP00000264866.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764C>A (p.A255E) alteration is located in exon 11 (coding exon 11) of the TBC1D19 gene. This alteration results from a C to A substitution at nucleotide position 764, causing the alanine (A) at amino acid position 255 to be replaced by a glutamic acid (E). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.053	.;T;.;.
Eigen	Benign	0.00094
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.;.
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.020	D;D;D;T
Sift4G	Uncertain	0.043	D;T;T;T
Polyphen		0.037	.;B;.;.
Vest4		0.63, 0.61
MutPred		0.46		.;Gain of solvent accessibility (P = 0.0145);.;.;
MVP		0.64
MPC		0.37
ClinPred		0.70	D
GERP RS		5.2
Varity_R		0.46
gMVP		0.54
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

hg19: chr4-26675458;