17-15740129-C-A

Variant names:

• chr17-15740129-C-A
• rs758806406
• NM_001388465.1:c.527C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001388465.1(TBC1D26):​c.527C>A​(p.Ala176Asp) 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 pathogenic outcome for this variant. 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: 2.34
• Publications: 1 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388465.1. 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
	TBC1D26	NM_001388465.1	MANE Select	c.527C>A	p.Ala176Asp	missense	Exon 9 of 15	NP_001375394.1	A0A8J8ZQP4
	TBC1D26	NM_178571.4		c.527C>A	p.Ala176Asp	missense	Exon 9 of 15	NP_848666.2	Q86UD7
	ZNF286A-TBC1D26	NR_171000.1		n.2716C>A		non_coding_transcript_exon	Exon 16 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D26	ENST00000437605.4	TSL:5 MANE Select	c.527C>A	p.Ala176Asp	missense	Exon 9 of 15	ENSP00000410111.3	A0A8J8ZQP4
	ZNF286A-TBC1D26	ENST00000413242.6	TSL:2	n.*1291C>A		non_coding_transcript_exon	Exon 11 of 17	ENSP00000458062.1
	TBC1D26	ENST00000469477.3	TSL:1	n.527C>A		non_coding_transcript_exon	Exon 9 of 16	ENSP00000434391.1	Q86UD7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0030	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		2.3
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.81		Loss of catalytic residue at S178 (P = 0.1605)
MVP		0.48
MPC		1.1
ClinPred		1.0	D
GERP RS		1.5
Varity_R		0.97
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758806406; hg19: chr17-15643443;