rs146791549

Variant names:

• chr3-17166860-C-G
• rs146791549
• NM_001349074.2:c.2067G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001349074.2(TBC1D5):​c.2067G>C​(p.Gln689His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,076 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q689R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TBC1D5 NM_001349074.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15791291).

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.2067G>C	p.Gln689His	missense	Exon 22 of 23	NP_001336003.1	Q92609-2
	TBC1D5	NM_001134381.2		c.2067G>C	p.Gln689His	missense	Exon 23 of 24	NP_001127853.1	Q92609-2
	TBC1D5	NM_001349073.2		c.2067G>C	p.Gln689His	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.2067G>C	p.Gln689His	missense	Exon 22 of 23	ENSP00000512418.1	Q92609-2
	TBC1D5	ENST00000446818.6	TSL:1	c.2067G>C	p.Gln689His	missense	Exon 23 of 24	ENSP00000402935.2	Q92609-2
	TBC1D5	ENST00000253692.11	TSL:1	c.2001G>C	p.Gln667His	missense	Exon 21 of 22	ENSP00000253692.6	Q92609-1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152246 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: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000994 AC: 25 AN: 251388 AF XY: 0.000103

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000202 AC: 296 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.000186 AC XY: 135 AN XY: 727222

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000259 AC: 288 AN: 1111986

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74386

African (AFR) AF: 0.0000965 AC: 4 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000382

EpiControl AF: 0.000296

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	0.22
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.079
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.94	P
Vest4		0.40
MutPred		0.18		Loss of sheet (P = 0.0817)
MVP		0.37
MPC		0.48
ClinPred		0.15	T
GERP RS		4.2
Varity_R		0.16
gMVP		0.39
Mutation Taster		=78/22	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: rs146791549; hg19: chr3-17208352;