4-6923417-A-G

Position:

• chr4-6923417-A-G

Variant summary

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

The NM_020773.3(TBC1D14):​c.28A>G​(p.Thr10Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D14 NM_020773.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.810

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=0.06892058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D14	NM_020773.3	c.28A>G	p.Thr10Ala	missense_variant	2/14	ENST00000409757.9	NP_065824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D14	ENST00000409757.9	c.28A>G	p.Thr10Ala	missense_variant	2/14	1	NM_020773.3	ENSP00000386921.4
TBC1D14	ENST00000448507.5	c.28A>G	p.Thr10Ala	missense_variant	2/14	5		ENSP00000404041.1
TBC1D14	ENST00000444368.1	c.28A>G	p.Thr10Ala	missense_variant	2/2	3		ENSP00000414951.1
TBC1D14	ENST00000427736.1	c.28A>G	p.Thr10Ala	missense_variant	2/2	2		ENSP00000411760.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 26, 2024

The c.28A>G (p.T10A) alteration is located in exon 2 (coding exon 1) of the TBC1D14 gene. This alteration results from a A to G substitution at nucleotide position 28, causing the threonine (T) at amino acid position 10 to be replaced by an alanine (A). 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	0.059
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.58	T;T;.;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.034
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.12, 0.16
MutPred		0.15		Loss of glycosylation at S9 (P = 0.0681);Loss of glycosylation at S9 (P = 0.0681);Loss of glycosylation at S9 (P = 0.0681);Loss of glycosylation at S9 (P = 0.0681);
MVP		0.54
MPC		0.28
ClinPred		0.15	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.14

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: rs1724017073; hg19: chr4-6925144;