NM_003193.5:c.100+48_100+65delGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-235380161-TTGTGTGTGTGTGTGTGTG-T
• rs10524346
• NM_003193.5:c.100+48_100+65delGTGTGTGTGTGTGTGTGT

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+48_100+65delGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 994,068 control chromosomes in the GnomAD database, including 3,019 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1832 hom., cov: 0)
  • Exomes 𝑓: 0.094 (3019 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-TTGTGTGTGTGTGTGTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTGTGTGTGTGTGTGTG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.100+48_100+65delGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.100+48_100+65delGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 17		NP_001274730.1
TBCE	NM_001079515.3	c.100+48_100+65delGTGTGTGTGTGTGTGTGT		intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2	c.-211+48_-211+65delGTGTGTGTGTGTGTGTGT		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+30delTGTGTGTGTGTGTGTGTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.100+13_100+30delTGTGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 18			ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 19663 AN: 139740 Hom.: 1830 Cov.: 0

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.128 AC: 22546 AN: 176408 AF XY: 0.122

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0680

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0936 AC: 93031 AN: 994068 Hom.: 3019 AF XY: 0.0969 AC XY: 49392 AN XY: 509514

African (AFR) AF: 0.130 AC: 3255 AN: 25014

American (AMR) AF: 0.214 AC: 8847 AN: 41428

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 1618 AN: 21030

East Asian (EAS) AF: 0.318 AC: 10777 AN: 33908

South Asian (SAS) AF: 0.179 AC: 13292 AN: 74404

European-Finnish (FIN) AF: 0.121 AC: 5578 AN: 46154

Middle Eastern (MID) AF: 0.119 AC: 533 AN: 4496

European-Non Finnish (NFE) AF: 0.0632 AC: 44505 AN: 704524

Other (OTH) AF: 0.107 AC: 4626 AN: 43110

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.141 AC: 19682 AN: 139862 Hom.: 1832 Cov.: 0 AF XY: 0.147 AC XY: 9857 AN XY: 67102

African (AFR) AF: 0.157 AC: 6022 AN: 38322

American (AMR) AF: 0.230 AC: 3111 AN: 13512

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 296 AN: 3316

East Asian (EAS) AF: 0.431 AC: 2042 AN: 4742

South Asian (SAS) AF: 0.271 AC: 1109 AN: 4086

European-Finnish (FIN) AF: 0.139 AC: 1156 AN: 8332

Middle Eastern (MID) AF: 0.115 AC: 32 AN: 278

European-Non Finnish (NFE) AF: 0.0865 AC: 5577 AN: 64492

Other (OTH) AF: 0.131 AC: 249 AN: 1904

Alfa AF: 0.0929 Hom.: 546

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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;