chr1-235379947-CAAAA-C

Variant names:

• chr1-235379947-CAAAA-C
• rs36068852
• NM_003193.5:c.-31-58_-31-55delAAAA

Variant summary

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

The NM_003193.5(TBCE):​c.-31-58_-31-55delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 596,186 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: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000081 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.566
• 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), PanelApp Australia, Orphanet, G2P
• 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, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, G2P, Ambry Genetics
• autosomal recessive Kenny-Caffey syndrome

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

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003193.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	NM_003193.5	MANE Select	c.-31-58_-31-55delAAAA		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.-31-58_-31-55delAAAA		intron	N/A	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.-31-58_-31-55delAAAA		intron	N/A	NP_001072983.1	Q15813-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	ENST00000642610.2	MANE Select	c.-31-71_-31-68delAAAA		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.-31-71_-31-68delAAAA		intron	N/A	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.-31-71_-31-68delAAAA		intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 132766 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: 0.0000805 AC: 48 AN: 596186 Hom.: 0 AF XY: 0.0000798 AC XY: 25 AN XY: 313424

⚠️ 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: 12776

American (AMR) AF: 0.0000799 AC: 2 AN: 25018

Ashkenazi Jewish (ASJ) AF: 0.000213 AC: 3 AN: 14116

East Asian (EAS) AF: 0.0000951 AC: 2 AN: 21022

South Asian (SAS) AF: 0.0000520 AC: 3 AN: 57686

European-Finnish (FIN) AF: 0.0000419 AC: 1 AN: 23840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3066

European-Non Finnish (NFE) AF: 0.0000801 AC: 33 AN: 412010

Other (OTH) AF: 0.000150 AC: 4 AN: 26652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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: 132766 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 63054

African (AFR) AF: 0.00 AC: 0 AN: 35968

American (AMR) AF: 0.00 AC: 0 AN: 12748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3284

East Asian (EAS) AF: 0.00 AC: 0 AN: 4542

South Asian (SAS) AF: 0.00 AC: 0 AN: 3992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62172

Other (OTH) AF: 0.00 AC: 0 AN: 1800

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs36068852; hg19: chr1-235543262;