NM_001349074.2:c.2203G>T

Variant names:

• chr3-17161214-C-A
• rs200832725
• NM_001349074.2:c.2203G>T

Variant summary

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

The NM_001349074.2(TBC1D5):​c.2203G>T​(p.Asp735Tyr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D735N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D5 NM_001349074.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20
• Publications: 0 publications found

Genes affected

TBC1D5 (HGNC:19166): (TBC1 domain family member 5) Enables AP-2 adaptor complex binding activity and retromer complex binding activity. Involved in several processes, including macroautophagy; positive regulation of receptor internalization; and retrograde transport, endosome to Golgi. Located in Golgi apparatus; autophagosome; and endosome membrane. Part of retromer complex. Colocalizes with AP-2 adaptor complex and Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285731 (HGNC:):

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=0.40166155).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349074.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D5	NM_001349074.2	MANE Select	c.2203G>T	p.Asp735Tyr	missense	Exon 23 of 23	NP_001336003.1	Q92609-2
	TBC1D5	NM_001134381.2		c.2203G>T	p.Asp735Tyr	missense	Exon 24 of 24	NP_001127853.1	Q92609-2
	TBC1D5	NM_001349073.2		c.2203G>T	p.Asp735Tyr	missense	Exon 22 of 22	NP_001336002.1	Q92609-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D5	ENST00000696125.1	MANE Select	c.2203G>T	p.Asp735Tyr	missense	Exon 23 of 23	ENSP00000512418.1	Q92609-2
	TBC1D5	ENST00000446818.6	TSL:1	c.2203G>T	p.Asp735Tyr	missense	Exon 24 of 24	ENSP00000402935.2	Q92609-2
	TBC1D5	ENST00000253692.11	TSL:1	c.2137G>T	p.Asp713Tyr	missense	Exon 22 of 22	ENSP00000253692.6	Q92609-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.32		Gain of phosphorylation at D713 (P = 0.0248)
MVP		0.58
MPC		0.66
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.76
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

dbSNP: rs200832725; hg19: chr3-17202706;