chr3-17161214-C-T

Variant names:

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

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.2203G>A​(p.Asp735Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TBC1D5 NM_001349074.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16489837).

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>A	p.Asp735Asn	missense	Exon 23 of 23	NP_001336003.1	Q92609-2
	TBC1D5	NM_001134381.2		c.2203G>A	p.Asp735Asn	missense	Exon 24 of 24	NP_001127853.1	Q92609-2
	TBC1D5	NM_001349073.2		c.2203G>A	p.Asp735Asn	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>A	p.Asp735Asn	missense	Exon 23 of 23	ENSP00000512418.1	Q92609-2
	TBC1D5	ENST00000446818.6	TSL:1	c.2203G>A	p.Asp735Asn	missense	Exon 24 of 24	ENSP00000402935.2	Q92609-2
	TBC1D5	ENST00000253692.11	TSL:1	c.2137G>A	p.Asp713Asn	missense	Exon 22 of 22	ENSP00000253692.6	Q92609-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249860 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461746 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727176

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111982

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.037
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.059
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.075	T
Polyphen		0.10	B
Vest4		0.27
MVP		0.44
MPC		0.16
ClinPred		0.25	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.64
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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; COSMIC: COSV99511064;