chr17-82938132-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_005993.5(TBCD):c.3365C>T(p.Pro1122Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,611,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1122P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TBCD
NM_005993.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.07

Publications

6 publications found

Variant links:

Genes affected

TBCD (HGNC:11581): (tubulin folding cofactor D) Cofactor D 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. [provided by RefSeq, Jul 2008]

TBCD Gene-Disease associations (from GenCC):

early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

TBCD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

PP5

Variant 17-82938132-C-T is Pathogenic according to our data. Variant chr17-82938132-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 268171.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCD	NM_005993.5 link	c.3365C>T	p.Pro1122Leu	missense_variant	Exon 36 of 39	ENST00000355528.9	NP_005984.3	Q9BTW9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCD	ENST00000355528.9 link	c.3365C>T	p.Pro1122Leu	missense_variant	Exon 36 of 39	1	NM_005993.5	ENSP00000347719.4		Q9BTW9-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000690

AC:

AN:

246440

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.0000661

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000301

Gnomad EAS exome

AF:

0.000615

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1459524

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726004

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.000345

AC:

AN:

26104

East Asian (EAS)

AF:

0.000176

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4682

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111744

Other (OTH)

AF:

0.0000166

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

Pathogenic:2Uncertain:1

Apr 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TBCD c.3365C>T (p.Pro1122Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 246440 control chromosomes (gnomAD). c.3365C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Encephalopathy, Early Onset and was shown to segregate with disease within affected families (Flex_2016, Miyake_2016, Tian_2019, Wojcik_2019, Chen_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated an extremely reduced TBCD protein level and partial loss of protein binding capacity with other components (Flex_2016, Miyake_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Pro1122Leu variant in TBCD was identified by our study, in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with arthrogryposis multiplex congenita with severe hypotonia, respiratory insufficiency, multiple brain abnormalities, polyneuropathy. The p.Pro1122Leu variant in TBCD has been reported in 7 individuals, including the proband mentioned above, with progressive, early-onset encephalopathy, with brain atrophy and thin corpus callosum (PMID: 31395954, 31240573, 27666374, 27666370) and segregated with disease in 2 affected relatives from 2 families (PMID: 27666374, 27666370). The presence of this variant in 2 affected homozygotes and in combination with reported variants of uncertain significance that are confirmed in trans, and in 5 individuals with encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum increases the likelihood that the p.Pro1122Leu variant is pathogenic (VariationID: 268170, 393181, 268173; PMID: 31395954, 31240573, 27666374, 27666370). This variant has also been reported in ClinVar as pathogenic by OMIM (Variation ID#: 268171). The p.Pro1122Leu variant has been identified in 0.06% (12/19446) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755177846). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies provide some evidence that the p.Pro1122Leu variant may impact protein function (PMID: 27666374, 27666370). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PS3_moderate, PP1 (Richards 2015). -

Nov 16, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1122 of the TBCD protein (p.Pro1122Leu). This variant is present in population databases (rs755177846, gnomAD 0.06%). This missense change has been observed in individual(s) with progressive early-onset encephalopathy with brain atrophy and thin corpus callosum (PMID: 27666370, 27666374, 31395954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 268171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBCD protein function. Experimental studies have shown that this missense change affects TBCD function (PMID: 27666370). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

2.9

M;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.8

D;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.12

T;.;.

Sift4G

Benign

0.069

T;T;D

Polyphen

1.0

D;.;.

Vest4

0.76

MutPred

0.67

Gain of sheet (P = 0.0266);.;.;

MVP

0.83

MPC

0.95

ClinPred

0.56

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.67

Mutation Taster

=4/96

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over