NM_001349074.2:c.2101G>C

Variant names:

• chr3-17166826-C-G
• rs754841258
• NM_001349074.2:c.2101G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001349074.2(TBC1D5):​c.2101G>C​(p.Gly701Arg) 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. 16/22 in silico tools predict 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. G701S) 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: 1.82
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104147226).

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.2101G>C	p.Gly701Arg	missense	Exon 22 of 23	NP_001336003.1	Q92609-2
	TBC1D5	NM_001134381.2		c.2101G>C	p.Gly701Arg	missense	Exon 23 of 24	NP_001127853.1	Q92609-2
	TBC1D5	NM_001349073.2		c.2101G>C	p.Gly701Arg	missense	Exon 21 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.2101G>C	p.Gly701Arg	missense	Exon 22 of 23	ENSP00000512418.1	Q92609-2
	TBC1D5	ENST00000446818.6	TSL:1	c.2101G>C	p.Gly701Arg	missense	Exon 23 of 24	ENSP00000402935.2	Q92609-2
	TBC1D5	ENST00000253692.11	TSL:1	c.2035G>C	p.Gly679Arg	missense	Exon 21 of 22	ENSP00000253692.6	Q92609-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.079
Sift	Benign	0.39	T
Sift4G	Benign	0.51	T
Polyphen		0.73	P
Vest4		0.20
MutPred		0.17		Gain of MoRF binding (P = 0.0273)
MVP		0.66
MPC		0.50
ClinPred		0.74	D
GERP RS		4.1
Varity_R		0.024
gMVP		0.28
Mutation Taster		=90/10	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

dbSNP: rs754841258; hg19: chr3-17208318;