4-6923741-A-C

Position:

• chr4-6923741-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020773.3(TBC1D14):​c.352A>C​(p.Thr118Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBC1D14 NM_020773.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

Genes affected

TBC1D14 (HGNC:29246): (TBC1 domain family member 14) Enables protein kinase binding activity. Involved in negative regulation of autophagy; recycling endosome to Golgi transport; and regulation of autophagosome assembly. Located in several cellular components, including Golgi apparatus; autophagosome; and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07639122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D14	NM_020773.3	c.352A>C	p.Thr118Pro	missense_variant	2/14	ENST00000409757.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D14	ENST00000409757.9	c.352A>C	p.Thr118Pro	missense_variant	2/14	1	NM_020773.3
TBC1D14	ENST00000448507.5	c.352A>C	p.Thr118Pro	missense_variant	2/14	5
TBC1D14	ENST00000444368.1	c.352A>C	p.Thr118Pro	missense_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.352A>C (p.T118P) alteration is located in exon 2 (coding exon 1) of the TBC1D14 gene. This alteration results from a A to C substitution at nucleotide position 352, causing the threonine (T) at amino acid position 118 to be replaced by a proline (P). 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	0.055
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.015
DANN	Benign	0.85
DEOGEN2	Benign	0.028	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.30	T;T;.
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.035
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.043	D;T;T
Polyphen		0.090	.;B;B
Vest4		0.11, 0.12
MutPred		0.080		Loss of phosphorylation at T118 (P = 0.01);Loss of phosphorylation at T118 (P = 0.01);Loss of phosphorylation at T118 (P = 0.01);
MVP		0.26
MPC		0.37
ClinPred		0.082	T
GERP RS		-3.9
Varity_R		0.052
gMVP		0.17

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

Other links and lift over

dbSNP: rs1724049625; hg19: chr4-6925468;