4-6923403-A-G

Position:

• chr4-6923403-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.14A>G​(p.Lys5Arg) 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: 33)
• Consequence: TBC1D14 NM_020773.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

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=0.096946985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D14	NM_020773.3	c.14A>G	p.Lys5Arg	missense_variant	2/14	ENST00000409757.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D14	ENST00000409757.9	c.14A>G	p.Lys5Arg	missense_variant	2/14	1	NM_020773.3
TBC1D14	ENST00000448507.5	c.14A>G	p.Lys5Arg	missense_variant	2/14	5
TBC1D14	ENST00000444368.1	c.14A>G	p.Lys5Arg	missense_variant	2/2	3
TBC1D14	ENST00000427736.1	c.14A>G	p.Lys5Arg	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 07, 2021

The c.14A>G (p.K5R) 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 14, causing the lysine (K) at amino acid position 5 to be replaced by an arginine (R). 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	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T;T;.;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.097	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.36	N;N;N;N
REVEL	Benign	0.074
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;T
Polyphen		0.0070	.;B;B;.
Vest4		0.21, 0.23
MutPred		0.10		Loss of ubiquitination at G5 (P = 0.0039);Loss of ubiquitination at G5 (P = 0.0039);Loss of ubiquitination at G5 (P = 0.0039);Loss of ubiquitination at G5 (P = 0.0039);
MVP		0.43
MPC		0.24
ClinPred		0.51	D
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.097

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-6925130;