dbSNP rs1478154983: TBCE:p.Lys475_Pro485dup (chr1-235448371-G-GAAGGGATTGCTGTCACGTCTTCTCAAAGTTCCT) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_003193.5(TBCE):c.1423_1455dupAAGGGATTGCTGTCACGTCTTCTCAAAGTTCCT(p.Lys475_Pro485dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000479 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TBCE
NM_003193.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.46

Variant links:

Genes affected

TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

TBCE links:

ENSG00000285053 (HGNC:):

ENSG00000285053 links:

B3GALNT2 (HGNC:28596): (beta-1,3-N-acetylgalactosaminyltransferase 2) This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel carbohydrate structure, on N- and O-glycans. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2013]

B3GALNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_003193.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5 link	c.1423_1455dupAAGGGATTGCTGTCACGTCTTCTCAAAGTTCCT	p.Lys475_Pro485dup	conservative_inframe_insertion	Exon 16 of 17	ENST00000642610.2	NP_003184.1	Q15813-1
B3GALNT2	NM_152490.5 link	c.1802_1834dupAGGAACTTTGAGAAGACGTGACAGCAATCCCTT		3_prime_UTR_variant	Exon 12 of 12	ENST00000366600.8	NP_689703.1	Q8NCR0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBCE	ENST00000642610.2 link	c.1423_1455dupAAGGGATTGCTGTCACGTCTTCTCAAAGTTCCT	p.Lys475_Pro485dup	conservative_inframe_insertion	Exon 16 of 17		NM_003193.5	ENSP00000494796.1	Q15813-1
ENSG00000285053	ENST00000645655.1 link	c.1423_1455dupAAGGGATTGCTGTCACGTCTTCTCAAAGTTCCT	p.Lys475_Pro485dup	conservative_inframe_insertion	Exon 19 of 20			ENSP00000495202.1	Q15813-1
B3GALNT2	ENST00000366600 link	c.1802_1834dupAGGAACTTTGAGAAGACGTGACAGCAATCCCTT		3_prime_UTR_variant	Exon 12 of 12	1	NM_152490.5	ENSP00000355559.3	Q8NCR0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250444

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame duplication of 11 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1423_1455dup, results in the insertion of 11 amino acid(s) of the TBCE protein (p.Lys475_Pro485dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TBCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 1491529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1423_1455dupAAGGGATTGCTGTCACGTCTTCTCAAAGTTCCT (p.K475_P485dup) alteration is located in exon 16 (coding exon 15) of the TBCE gene. The alteration consists of an in-frame duplication of 33 nucleotides from position 1423 to 1455, resulting in the duplication of <NA> residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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