1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr1-235380161-TTGTGTGTGTGTGTGTG-T
• rs10524346
• NM_003193.5:c.100+50_100+65delGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003193.5(TBCE):​c.100+50_100+65delGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0706 in 1,130,276 control chromosomes in the GnomAD database, including 1,213 homozygotes. 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (203 hom., cov: 0)
  • Exomes 𝑓: 0.074 (1010 hom.)
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.667
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-235380161-TTGTGTGTGTGTGTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTGTGTGTGTGTGTG-T is described in ClinVar as Benign. ClinVar VariationId is 1232644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.100+50_100+65delGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.100+50_100+65delGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 17		NP_001274730.1
TBCE	NM_001079515.3	c.100+50_100+65delGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2	c.-211+50_-211+65delGTGTGTGTGTGTGTGT		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+28delTGTGTGTGTGTGTGTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.100+13_100+28delTGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 18			ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6359 AN: 139712 Hom.: 199 Cov.: 0

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.0820

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.0895

Gnomad SAS AF: 0.0421

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0506

GnomAD2 exomes AF: 0.0770 AC: 13578 AN: 176408 AF XY: 0.0780

Gnomad AFR exome AF: 0.0784

Gnomad AMR exome AF: 0.0478

Gnomad ASJ exome AF: 0.0859

Gnomad EAS exome AF: 0.0847

Gnomad FIN exome AF: 0.0866

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0741 AC: 73382 AN: 990442 Hom.: 1010 AF XY: 0.0746 AC XY: 37872 AN XY: 507668

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

African (AFR) AF: 0.0705 AC: 1760 AN: 24978

American (AMR) AF: 0.0466 AC: 1929 AN: 41410

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 1873 AN: 20906

East Asian (EAS) AF: 0.0835 AC: 2827 AN: 33848

South Asian (SAS) AF: 0.0486 AC: 3621 AN: 74516

European-Finnish (FIN) AF: 0.0979 AC: 4488 AN: 45856

Middle Eastern (MID) AF: 0.0992 AC: 441 AN: 4444

European-Non Finnish (NFE) AF: 0.0755 AC: 52939 AN: 701524

Other (OTH) AF: 0.0816 AC: 3504 AN: 42960

⚠️ 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 AF: 0.0456 AC: 6379 AN: 139834 Hom.: 203 Cov.: 0 AF XY: 0.0461 AC XY: 3090 AN XY: 67078

African (AFR) AF: 0.0759 AC: 2909 AN: 38348

American (AMR) AF: 0.0325 AC: 439 AN: 13522

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 149 AN: 3314

East Asian (EAS) AF: 0.0895 AC: 425 AN: 4748

South Asian (SAS) AF: 0.0423 AC: 173 AN: 4086

European-Finnish (FIN) AF: 0.0337 AC: 279 AN: 8290

Middle Eastern (MID) AF: 0.0827 AC: 23 AN: 278

European-Non Finnish (NFE) AF: 0.0281 AC: 1811 AN: 64470

Other (OTH) AF: 0.0521 AC: 99 AN: 1900

Alfa AF: 0.0916 Hom.: 546

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

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;