1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr1-235380161-TTGTGTGTG-T
• rs10524346
• NM_003193.5:c.100+58_100+65delGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003193.5(TBCE):​c.100+58_100+65delGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,135,460 control chromosomes in the GnomAD database, including 80 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (43 hom., cov: 0)
  • Exomes 𝑓: 0.014 (37 hom.)
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 1-235380161-TTGTGTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTGTGTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1563247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0224 (3140/139880) while in subpopulation AFR AF = 0.0331 (1267/38324). AF 95% confidence interval is 0.0315. There are 43 homozygotes in GnomAd4. There are 1472 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.100+58_100+65delGTGTGTGT		intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.100+58_100+65delGTGTGTGT		intron_variant	Intron 2 of 17		NP_001274730.1
TBCE	NM_001079515.3	c.100+58_100+65delGTGTGTGT		intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2	c.-211+58_-211+65delGTGTGTGT		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+20delTGTGTGTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.100+13_100+20delTGTGTGTG		intron_variant	Intron 4 of 18			ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3131 AN: 139758 Hom.: 44 Cov.: 0

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00342

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0175

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.0100

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0170

GnomAD4 exome AF: 0.0135 AC: 13463 AN: 995580 Hom.: 37 AF XY: 0.0142 AC XY: 7265 AN XY: 510176

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

African (AFR) AF: 0.0170 AC: 426 AN: 25058

American (AMR) AF: 0.00813 AC: 337 AN: 41474

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 340 AN: 21032

East Asian (EAS) AF: 0.0305 AC: 1030 AN: 33822

South Asian (SAS) AF: 0.0271 AC: 2015 AN: 74236

European-Finnish (FIN) AF: 0.00904 AC: 419 AN: 46366

Middle Eastern (MID) AF: 0.0229 AC: 103 AN: 4500

European-Non Finnish (NFE) AF: 0.0116 AC: 8159 AN: 705912

Other (OTH) AF: 0.0147 AC: 634 AN: 43180

⚠️ 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: 0.0224 AC: 3140 AN: 139880 Hom.: 43 Cov.: 0 AF XY: 0.0219 AC XY: 1472 AN XY: 67104

African (AFR) AF: 0.0331 AC: 1267 AN: 38324

American (AMR) AF: 0.0154 AC: 208 AN: 13526

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 58 AN: 3314

East Asian (EAS) AF: 0.0234 AC: 111 AN: 4740

South Asian (SAS) AF: 0.0228 AC: 93 AN: 4086

European-Finnish (FIN) AF: 0.00623 AC: 52 AN: 8350

Middle Eastern (MID) AF: 0.0108 AC: 3 AN: 278

European-Non Finnish (NFE) AF: 0.0204 AC: 1313 AN: 64480

Other (OTH) AF: 0.0168 AC: 32 AN: 1904

Alfa AF: 0.00 Hom.: 546

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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

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;