1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_003193.5(TBCE):c.100+64_100+65dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.019 ( 32 hom., cov: 0)

Exomes 𝑓: 0.0045 ( 0 hom. )

Consequence

TBCE
NM_003193.5 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.401

Publications

1 publications found

Variant links:

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

TBCE links:

ENSG00000285053 (HGNC:):

ENSG00000285053 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 1-235380161-T-TTG is Benign according to our data. Variant chr1-235380161-T-TTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296289.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2678/139848) while in subpopulation NFE AF = 0.0276 (1777/64456). AF 95% confidence interval is 0.0265. There are 32 homozygotes in GnomAd4. There are 1206 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5 link	c.100+64_100+65dupGT	intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1	Q15813-1
TBCE	NM_001287801.2 link	c.100+64_100+65dupGT	intron_variant	Intron 2 of 17		NP_001274730.1	Q15813-2
TBCE	NM_001079515.3 link	c.100+64_100+65dupGT	intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2 link	c.-211+64_-211+65dupGT	intron_variant	Intron 2 of 15		NP_001274731.1	Q15813A0A2R8Y6Q1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2 link	c.100+12_100+13insTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1		Q15813-1
ENSG00000285053	ENST00000647186.1 link	c.100+12_100+13insTG		intron_variant	Intron 4 of 18			ENSP00000494775.1		Q15813-1

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2676

AN:

139726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00685

Gnomad AMI

AF:

0.00683

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.0139

Gnomad SAS

AF:

0.0113

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.0133

Gnomad NFE

AF:

0.0276

Gnomad OTH

AF:

0.0186

GnomAD4 exome

AF:

0.00445

AC:

4436

AN:

996812

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

2367

AN XY:

510910

show subpopulations

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

African (AFR)

AF:

0.00143

AC:

AN:

25156

American (AMR)

AF:

0.00518

AC:

215

AN:

41510

Ashkenazi Jewish (ASJ)

AF:

0.00408

AC:

AN:

21080

East Asian (EAS)

AF:

0.00342

AC:

116

AN:

33962

South Asian (SAS)

AF:

0.00485

AC:

362

AN:

74688

European-Finnish (FIN)

AF:

0.00507

AC:

235

AN:

46380

Middle Eastern (MID)

AF:

0.00422

AC:

AN:

4502

European-Non Finnish (NFE)

AF:

0.00445

AC:

3144

AN:

706278

Other (OTH)

AF:

0.00516

AC:

223

AN:

43256

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.322

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2678

AN:

139848

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1206

AN XY:

67078

show subpopulations

African (AFR)

AF:

0.00683

AC:

262

AN:

38350

American (AMR)

AF:

0.0229

AC:

309

AN:

13500

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3312

East Asian (EAS)

AF:

0.0139

AC:

AN:

4748

South Asian (SAS)

AF:

0.0113

AC:

AN:

4084

European-Finnish (FIN)

AF:

0.0162

AC:

135

AN:

8336

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0276

AC:

1777

AN:

64456

Other (OTH)

AF:

0.0184

AC:

AN:

1906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypoparathyroidism-retardation-dysmorphism syndrome

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 29, 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

-0.40

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over