17-82905981-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005993.5(TBCD):c.1850T>C(p.Met617Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,607,640 control chromosomes in the GnomAD database, including 157,642 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M617R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.48 ( 18827 hom., cov: 34)

Exomes 𝑓: 0.43 ( 138815 hom. )

Consequence

TBCD
NM_005993.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.106

Publications

50 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.391527E-6).

BP6

Variant 17-82905981-T-C is Benign according to our data. Variant chr17-82905981-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCD	NM_005993.5 link	c.1850T>C	p.Met617Thr	missense_variant	Exon 20 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.1850T>C	p.Met617Thr	missense_variant	Exon 20 of 39	1	NM_005993.5	ENSP00000347719.4		Q9BTW9-1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73650

AN:

151994

Hom.:

18812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.656

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.414

Gnomad ASJ

AF:

0.488

Gnomad EAS

AF:

0.287

Gnomad SAS

AF:

0.538

Gnomad FIN

AF:

0.408

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.468

GnomAD2 exomes

AF:

0.438

AC:

107922

AN:

246480

AF XY:

0.443

show subpopulations

Gnomad AFR exome

AF:

0.662

Gnomad AMR exome

AF:

0.373

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.414

Gnomad NFE exome

AF:

0.427

Gnomad OTH exome

AF:

0.446

GnomAD4 exome

AF:

0.433

AC:

629770

AN:

1455528

Hom.:

138815

Cov.:

AF XY:

0.435

AC XY:

315065

AN XY:

723978

show subpopulations

African (AFR)

AF:

0.667

AC:

22224

AN:

33300

American (AMR)

AF:

0.383

AC:

17029

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

12638

AN:

26110

East Asian (EAS)

AF:

0.258

AC:

10215

AN:

39644

South Asian (SAS)

AF:

0.536

AC:

46075

AN:

85890

European-Finnish (FIN)

AF:

0.416

AC:

22097

AN:

53152

Middle Eastern (MID)

AF:

0.538

AC:

3098

AN:

5760

European-Non Finnish (NFE)

AF:

0.424

AC:

469439

AN:

1107036

Other (OTH)

AF:

0.448

AC:

26955

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

17790

35580

53371

71161

88951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14460

28920

43380

57840

72300

<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:

0.485

AC:

73705

AN:

152112

Hom.:

18827

Cov.:

AF XY:

0.482

AC XY:

35822

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.656

AC:

27221

AN:

41488

American (AMR)

AF:

0.414

AC:

6334

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.488

AC:

1694

AN:

3468

East Asian (EAS)

AF:

0.287

AC:

1486

AN:

5172

South Asian (SAS)

AF:

0.537

AC:

2593

AN:

4828

European-Finnish (FIN)

AF:

0.408

AC:

4317

AN:

10574

Middle Eastern (MID)

AF:

0.527

AC:

154

AN:

292

European-Non Finnish (NFE)

AF:

0.422

AC:

28699

AN:

67970

Other (OTH)

AF:

0.464

AC:

981

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1933

3867

5800

7734

9667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.444

Hom.:

52735

Bravo

AF:

0.491

TwinsUK

AF:

0.426

AC:

1579

ALSPAC

AF:

0.423

AC:

1630

ESP6500AA

AF:

0.674

AC:

2857

ESP6500EA

AF:

0.431

AC:

3645

ExAC

AF:

0.447

AC:

54064

Asia WGS

AF:

0.448

AC:

1555

AN:

3474

ClinVar

Significance: 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.13

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.014

T;.;.;.;T;T;.;T;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.023

T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0000044

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.3

N;.;.;.;.;.;.;.;.;.;.

PhyloP100

0.11

PrimateAI

Benign

0.35

PROVEAN

Benign

2.8

N;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.094

Sift

Benign

1.0

T;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.;.;.;.;.;.

Vest4

0.10

MPC

0.33

ClinPred

0.0024

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(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