Variant 6-121292052-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_152730.6(TBC1D32):c.1372+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000281 in 1,425,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TBC1D32
NM_152730.6 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.84

Variant links:

Genes affected

TBC1D32 (HGNC:21485): (TBC1 domain family member 32) This gene encodes a TBC-domain containing protein. Studies of a similar protein in mouse and zebrafish suggest that the encoded protein is involved in sonic hedgehog signaling, and that it interacts with and stabilizes cell cycle-related kinase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

TBC1D32 links:

TBC1D32 (HGNC:):

TBC1D32 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03709592 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-121292052-C-A is Pathogenic according to our data. Variant chr6-121292052-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 139613.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-121292052-C-A is described in Lovd as [Pathogenic]. Variant chr6-121292052-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D32	NM_152730.6 linkuse as main transcript	c.1372+1G>T		splice_donor_variant, intron_variant		ENST00000398212.7	NP_689943.4	Q96NH3-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
TBC1D32	ENST00000398212.7 linkuse as main transcript	c.1372+1G>T	splice_donor_variant, intron_variant	5	NM_152730.6	ENSP00000381270.2	Q96NH3-1
TBC1D32	ENST00000275159.11 linkuse as main transcript	c.1372+1G>T	splice_donor_variant, intron_variant	5		ENSP00000275159.6	Q96NH3-4
TBC1D32	ENST00000464622.5 linkuse as main transcript	n.*1063+1G>T	splice_donor_variant, intron_variant	2		ENSP00000428839.1	Q96NH3-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000436

AC:

AN:

229504

Hom.:

AF XY:

0.00000803

AC XY:

AN XY:

124460

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000597

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1425684

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

708278

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000512

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2023	Published functional studies demonstrate skipping of exon 12 leading to an in-frame truncation of 47 amino acids (Adly et al., 2014; Maddirevula et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32552793, 27894351, 29450879, 24285566, 31130284) -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.97

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 2

DS_DL_spliceai

0.99

Position offset: 1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over