dbSNP rs35579976: TBCE:p.Ser333Thr (chr1-235437356-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003193.5(TBCE):c.998G>C(p.Ser333Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,614,094 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 26 hom. )

Consequence

TBCE
NM_003193.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.98

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008432835).

BP6

Variant 1-235437356-G-C is Benign according to our data. Variant chr1-235437356-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00939 (1429/152222) while in subpopulation AFR AF = 0.0327 (1360/41528). AF 95% confidence interval is 0.0313. There are 21 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003193.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBCE	NM_003193.5	MANE Select	c.998G>C	p.Ser333Thr	missense	Exon 12 of 17	NP_003184.1
TBCE	NM_001287801.2		c.1151G>C	p.Ser384Thr	missense	Exon 13 of 18	NP_001274730.1
TBCE	NM_001079515.3		c.998G>C	p.Ser333Thr	missense	Exon 12 of 17	NP_001072983.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBCE	ENST00000642610.2	MANE Select	c.998G>C	p.Ser333Thr	missense	Exon 12 of 17	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1		c.998G>C	p.Ser333Thr	missense	Exon 14 of 19	ENSP00000494775.1
TBCE	ENST00000366601.8	TSL:1	c.809G>C	p.Ser270Thr	missense	Exon 10 of 15	ENSP00000355560.4

Frequencies

GnomAD3 genomes

AF:

0.00939

AC:

1428

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00252

AC:

633

AN:

251494

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.0342

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000995

AC:

1454

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

634

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0354

AC:

1186

AN:

33480

American (AMR)

AF:

0.00195

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000104

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112002

Other (OTH)

AF:

0.00258

AC:

156

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00939

AC:

1429

AN:

152222

Hom.:

Cov.:

AF XY:

0.00896

AC XY:

667

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0327

AC:

1360

AN:

41528

American (AMR)

AF:

0.00288

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00279

Hom.:

Bravo

AF:

0.0112

ESP6500AA

AF:

0.0279

AC:

123

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00307

AC:

373

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 29, 2015

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypoparathyroidism-retardation-dysmorphism syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.13

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PhyloP100

2.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

REVEL

Benign

0.061

Sift

Benign

0.13

Sift4G

Benign

0.53

Polyphen

0.26

Vest4

0.33

MVP

0.33

MPC

0.38

ClinPred

0.024

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.51

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over