17-15741159-C-T

Variant names:

• chr17-15741159-C-T
• NM_001388465.1:c.584C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001388465.1(TBC1D26):​c.584C>T​(p.Ala195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D26 NM_001388465.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.649

Genes affected

TBC1D26 (HGNC:28745): (TBC1 domain family member 26) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. [provided by Alliance of Genome Resources, Apr 2022]

ZNF286A-TBC1D26 (HGNC:55384): (ZNF286A-TBC1D26 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring ZNF286A and TBC1D26 genes. This transcript is thought to be non-coding because it would be subject to nonsense-mediated mRNA decay (NMD). [provided by RefSeq, Nov 2020]

TBC1D26-AS1 (HGNC:41211): (TBC1D26 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D26	NM_001388465.1	c.584C>T	p.Ala195Val	missense_variant	Exon 10 of 15	ENST00000437605.4	NP_001375394.1
TBC1D26	NM_178571.4	c.584C>T	p.Ala195Val	missense_variant	Exon 10 of 15		NP_848666.2
ZNF286A-TBC1D26	NR_171000.1	n.2773C>T		non_coding_transcript_exon_variant	Exon 17 of 23
TBC1D26-AS1	XR_001753084.3	n.149+2444G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D26	ENST00000437605.4	c.584C>T	p.Ala195Val	missense_variant	Exon 10 of 15	5	NM_001388465.1	ENSP00000410111.3
ZNF286A-TBC1D26	ENST00000413242.6	n.*1348C>T		non_coding_transcript_exon_variant	Exon 12 of 17	2		ENSP00000458062.1
ZNF286A-TBC1D26	ENST00000413242.6	n.*1348C>T		3_prime_UTR_variant	Exon 12 of 17	2		ENSP00000458062.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.584C>T (p.A195V) alteration is located in exon 10 (coding exon 8) of the TBC1D26 gene. This alteration results from a C to T substitution at nucleotide position 584, causing the alanine (A) at amino acid position 195 to be replaced by a valine (V). 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	Benign	0.28
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.014
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.75		Loss of catalytic residue at A195 (P = 0.1735);
MVP		0.57
MPC		0.47
ClinPred		0.96	D
GERP RS		0.71
Varity_R		0.69
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-15644473;