1-235448358-C-CAATTCAAAAGGTGAAGGGATTGCTG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003193.5(TBCE):c.1410_1434dup(p.Ser479AsnfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBCE NM_003193.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0670

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCE	NM_003193.5	c.1410_1434dup	p.Ser479AsnfsTer24	frameshift_variant	16/17	ENST00000642610.2
B3GALNT2	NM_152490.5	c.*1847_*1848insCAGCAATCCCTTCACCTTTTGAATT		3_prime_UTR_variant	12/12	ENST00000366600.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCE	ENST00000642610.2	c.1410_1434dup	p.Ser479AsnfsTer24	frameshift_variant	16/17		NM_003193.5	P1
B3GALNT2	ENST00000366600.8	c.*1847_*1848insCAGCAATCCCTTCACCTTTTGAATT		3_prime_UTR_variant	12/12	1	NM_152490.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151994 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250054 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135292

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: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000233 AC: 34 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727200

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: 0.0000306

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151994 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74210

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Encephalopathy, progressive, with amyotrophy and optic atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 26, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 16 of 17). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (P) 0600 - Variant is predicted to truncate part of the ubiquitin-like domain (PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1253540549; hg19: chr1-235611673;