6-121091045-TAAA-TAAAAAA

Variant names:

• chr6-121091045-T-TAAA
• rs397887772
• NM_152730.6:c.3466-7_3466-5dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152730.6(TBC1D32):​c.3466-7_3466-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,156,650 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TBC1D32 NM_152730.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.424
• Publications: 0 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: Illumina, G2P
• orofaciodigital syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• orofaciodigital syndrome IX

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
TBC1D32	NM_152730.6	c.3466-7_3466-5dupTTT		splice_region_variant, intron_variant	Intron 30 of 31	ENST00000398212.7	NP_689943.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D32	ENST00000398212.7	c.3466-5_3466-4insTTT		splice_region_variant, intron_variant	Intron 30 of 31	5	NM_152730.6	ENSP00000381270.2
TBC1D32	ENST00000275159.11	c.3589-5_3589-4insTTT		splice_region_variant, intron_variant	Intron 31 of 32	5		ENSP00000275159.6
TBC1D32	ENST00000464622.5	n.*4106-5_*4106-4insTTT		splice_region_variant, intron_variant	Intron 34 of 35	2		ENSP00000428839.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000740 AC: 1 AN: 135180 AF XY: 0.00

Gnomad AFR exome AF: 0.0000828

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000346 AC: 4 AN: 1156650 Hom.: 0 Cov.: 29 AF XY: 0.00000523 AC XY: 3 AN XY: 573552

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26418

American (AMR) AF: 0.00 AC: 0 AN: 27168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18568

East Asian (EAS) AF: 0.00 AC: 0 AN: 30676

South Asian (SAS) AF: 0.00 AC: 0 AN: 63242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4670

European-Non Finnish (NFE) AF: 0.00000445 AC: 4 AN: 898322

Other (OTH) AF: 0.00 AC: 0 AN: 47556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006674), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42

Splicing

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

Other links and lift over

dbSNP: rs397887772; hg19: chr6-121412191;