chr6-121091045-TA-T

Variant names:

• chr6-121091045-TA-T
• rs397887772
• NM_152730.6:c.3466-5delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_152730.6(TBC1D32):​c.3466-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,216,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 23)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: TBC1D32 NM_152730.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 0 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0193) population. However there is too low homozygotes in high coverage region: (expected more than 26, got 0).
• BP6: Variant 6-121091045-TA-T is Benign according to our data. Variant chr6-121091045-TA-T is described in ClinVar as [Benign]. Clinvar id is 1601435.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 73 AN: 147800 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00314

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000346

Gnomad OTH AF: 0.000497

GnomAD2 exomes AF: 0.0184 AC: 2492 AN: 135180 AF XY: 0.0193

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0107 AC: 11385 AN: 1068194 Hom.: 0 Cov.: 29 AF XY: 0.0112 AC XY: 5912 AN XY: 528776

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

African (AFR) AF: 0.00282 AC: 73 AN: 25896

American (AMR) AF: 0.00968 AC: 248 AN: 25630

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 266 AN: 16660

East Asian (EAS) AF: 0.0112 AC: 304 AN: 27194

South Asian (SAS) AF: 0.0202 AC: 1145 AN: 56578

European-Finnish (FIN) AF: 0.0141 AC: 513 AN: 36498

Middle Eastern (MID) AF: 0.00711 AC: 31 AN: 4360

European-Non Finnish (NFE) AF: 0.0100 AC: 8334 AN: 831458

Other (OTH) AF: 0.0107 AC: 471 AN: 43920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000494 AC: 73 AN: 147884 Hom.: 0 Cov.: 23 AF XY: 0.000500 AC XY: 36 AN XY: 72066

African (AFR) AF: 0.000442 AC: 18 AN: 40730

American (AMR) AF: 0.000201 AC: 3 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00315 AC: 16 AN: 5080

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4654

European-Finnish (FIN) AF: 0.00117 AC: 11 AN: 9370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000346 AC: 23 AN: 66524

Other (OTH) AF: 0.000493 AC: 1 AN: 2028

Alfa AF: 0.00614 Hom.: 60

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs397887772; hg19: chr6-121412191; COSMIC: COSV51553612; COSMIC: COSV51553612;