rs587777505

Variant names:

• chr6-121292052-C-A
• rs587777505
• NM_152730.6:c.1372+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-121292052-C-A
• chr6-121292052-C-G
• chr6-121292052-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_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 (★). ClinVar reports functional evidence for this variant: "SCV005325232: Published functional studies demonstrate skipping of exon 12 leading to an in-frame truncation of 47 amino acids (Adly et al., 2014" and additional evidence is available in ClinVar.

• 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:3
• Conservation: PhyloP100: 5.84
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Illumina
• orofaciodigital syndrome IX

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• orofaciodigital syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03736089 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005325232: 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)
• 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 VariationId is 139613.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152730.6. 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
	TBC1D32	NM_152730.6	MANE Select	c.1372+1G>T		splice_donor intron	N/A	NP_689943.4
	TBC1D32	NM_001367759.1		c.1372+1G>T		splice_donor intron	N/A	NP_001354688.1	Q96NH3-4
	TBC1D32	NM_001367760.1		c.1372+1G>T		splice_donor intron	N/A	NP_001354689.1	Q96NH3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D32	ENST00000398212.7	TSL:5 MANE Select	c.1372+1G>T		splice_donor intron	N/A	ENSP00000381270.2	Q96NH3-1
	TBC1D32	ENST00000275159.11	TSL:5	c.1372+1G>T		splice_donor intron	N/A	ENSP00000275159.6	Q96NH3-4
	TBC1D32	ENST00000464622.5	TSL:2	n.*1063+1G>T		splice_donor intron	N/A	ENSP00000428839.1	Q96NH3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000436 AC: 1 AN: 229504 AF XY: 0.00000803

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1425684 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 708278

African (AFR) AF: 0.00 AC: 0 AN: 31816

American (AMR) AF: 0.00 AC: 0 AN: 39190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25040

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39052

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5014

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094638

Other (OTH) AF: 0.0000170 AC: 1 AN: 58898

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Alsahan-Harris syndrome (1)
1	-	-	not provided (1)
1	-	-	Orofaciodigital syndrome IX (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		5.8
GERP RS		5.9
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs587777505; hg19: chr6-121613198;