3-17185147-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001349074.2(TBC1D5):​c.1880T>A​(p.Met627Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TBC1D5
NM_001349074.2 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.74
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBC1D5NM_001349074.2 linkuse as main transcriptc.1880T>A p.Met627Lys missense_variant 20/23 ENST00000696125.1 NP_001336003.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBC1D5ENST00000696125.1 linkuse as main transcriptc.1880T>A p.Met627Lys missense_variant 20/23 NM_001349074.2 ENSP00000512418 P2Q92609-2
ENST00000649558.1 linkuse as main transcriptn.699-18576A>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251358
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135830
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461390
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727020
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2022The c.1880T>A (p.M627K) alteration is located in exon 21 (coding exon 18) of the TBC1D5 gene. This alteration results from a T to A substitution at nucleotide position 1880, causing the methionine (M) at amino acid position 627 to be replaced by a lysine (K). 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
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.087
T;T;.;T
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D;D;D
M_CAP
Benign
0.049
D
MetaRNN
Pathogenic
0.83
D;D;D;D
MetaSVM
Benign
-0.50
T
MutationAssessor
Benign
1.8
L;L;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.4
D;D;D;D
REVEL
Uncertain
0.60
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.032
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.97
MutPred
0.61
Loss of stability (P = 0.0034);Loss of stability (P = 0.0034);.;.;
MVP
0.82
MPC
0.79
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.89
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs994977268; hg19: chr3-17226639; API