1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr1-235380161-TTGTGTG-T
• rs10524346
• NM_003193.5:c.100+60_100+65delGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003193.5(TBCE):​c.100+60_100+65delGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,131,738 control chromosomes in the GnomAD database, including 186 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (105 hom., cov: 0)
  • Exomes 𝑓: 0.024 (81 hom.)
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.504
• 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-TTGTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTGTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1608272.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.100+60_100+65delGTGTGT		intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.100+60_100+65delGTGTGT		intron_variant	Intron 2 of 17		NP_001274730.1
TBCE	NM_001079515.3	c.100+60_100+65delGTGTGT		intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2	c.-211+60_-211+65delGTGTGT		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+18delTGTGTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.100+13_100+18delTGTGTG		intron_variant	Intron 4 of 18			ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 4733 AN: 139682 Hom.: 105 Cov.: 0

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0115

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.0767

Gnomad NFE AF: 0.0403

Gnomad OTH AF: 0.0463

GnomAD4 exome AF: 0.0245 AC: 24269 AN: 991936 Hom.: 81 AF XY: 0.0269 AC XY: 13692 AN XY: 508078

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

African (AFR) AF: 0.0129 AC: 323 AN: 25050

American (AMR) AF: 0.0156 AC: 647 AN: 41350

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 728 AN: 20960

East Asian (EAS) AF: 0.0374 AC: 1257 AN: 33588

South Asian (SAS) AF: 0.0609 AC: 4476 AN: 73504

European-Finnish (FIN) AF: 0.0263 AC: 1214 AN: 46180

Middle Eastern (MID) AF: 0.0393 AC: 175 AN: 4458

European-Non Finnish (NFE) AF: 0.0203 AC: 14255 AN: 703838

Other (OTH) AF: 0.0278 AC: 1194 AN: 43008

⚠️ 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: 0.0339 AC: 4734 AN: 139802 Hom.: 105 Cov.: 0 AF XY: 0.0334 AC XY: 2237 AN XY: 67032

African (AFR) AF: 0.0186 AC: 712 AN: 38328

American (AMR) AF: 0.0286 AC: 386 AN: 13510

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 209 AN: 3312

East Asian (EAS) AF: 0.0259 AC: 123 AN: 4740

South Asian (SAS) AF: 0.0965 AC: 393 AN: 4074

European-Finnish (FIN) AF: 0.0234 AC: 195 AN: 8338

Middle Eastern (MID) AF: 0.0755 AC: 21 AN: 278

European-Non Finnish (NFE) AF: 0.0403 AC: 2598 AN: 64446

Other (OTH) AF: 0.0457 AC: 87 AN: 1904

Alfa AF: 0.0132 Hom.: 546

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2024

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		0.50
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;