chr1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-T

Variant names:

• chr1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-T
• rs10524346
• NM_003193.5:c.100+30_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

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

The NM_003193.5(TBCE):​c.100+30_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 998,894 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.667
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypoparathyroidism-retardation-dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• encephalopathy, progressive, with amyotrophy and optic atrophy

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
• autosomal recessive Kenny-Caffey syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.100+30_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.100+30_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 17		NP_001274730.1
TBCE	NM_001079515.3	c.100+30_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2	c.-211+30_-211+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 15		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2	c.100+13_100+48delTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.100+13_100+48delTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 18			ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 139842 Hom.: 0 Cov.: 0

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000501 AC: 5 AN: 998894 Hom.: 0 AF XY: 0.00000976 AC XY: 5 AN XY: 512068

⚠️ 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: 25168

American (AMR) AF: 0.00 AC: 0 AN: 41600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21144

East Asian (EAS) AF: 0.00 AC: 0 AN: 34036

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4514

European-Non Finnish (NFE) AF: 0.00000565 AC: 4 AN: 707706

Other (OTH) AF: 0.00 AC: 0 AN: 43370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0444683), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 139842 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67004

African (AFR) AF: 0.00 AC: 0 AN: 38248

American (AMR) AF: 0.00 AC: 0 AN: 13506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4758

South Asian (SAS) AF: 0.00 AC: 0 AN: 4090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64516

Other (OTH) AF: 0.00 AC: 0 AN: 1882

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67

Splicing

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

Other links and lift over

dbSNP: rs10524346; hg19: chr1-235543476;