chr3-17233704-C-G

Position:

• chr3-17233704-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001349074.2(TBC1D5):​c.1635G>C​(p.Gln545His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBC1D5 NM_001349074.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26482892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D5	NM_001349074.2	c.1635G>C	p.Gln545His	missense_variant	18/23	ENST00000696125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D5	ENST00000696125.1	c.1635G>C	p.Gln545His	missense_variant	18/23		NM_001349074.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

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

May 06, 2022

The c.1635G>C (p.Q545H) alteration is located in exon 19 (coding exon 16) of the TBC1D5 gene. This alteration results from a G to C substitution at nucleotide position 1635, causing the glutamine (Q) at amino acid position 545 to be replaced by a histidine (H). 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
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D;T
Sift4G	Benign	0.087	T;T
Polyphen		0.99	.;D
Vest4		0.27
MutPred		0.23		.;Gain of catalytic residue at L499 (P = 0.0615);
MVP		0.77
MPC		0.14
ClinPred		0.64	D
GERP RS		6.1
gMVP		0.41

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: chr3-17275196;