Genetic Variant NM_005993.5:c.2468C>A (chr17-82926488-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005993.5(TBCD):c.2468C>A(p.Ala823Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A823A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TBCD
NM_005993.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.63

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39002767).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005993.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBCD	NM_005993.5	MANE Select	c.2468C>A	p.Ala823Glu	missense	Exon 28 of 39	NP_005984.3
TBCD	NM_001411101.1		c.2417C>A	p.Ala806Glu	missense	Exon 27 of 38	NP_001398030.1
TBCD	NM_001411102.1		c.2387C>A	p.Ala796Glu	missense	Exon 27 of 38	NP_001398031.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBCD	ENST00000355528.9	TSL:1 MANE Select	c.2468C>A	p.Ala823Glu	missense	Exon 28 of 39	ENSP00000347719.4
TBCD	ENST00000571796.5	TSL:1	n.1126C>A		non_coding_transcript_exon	Exon 13 of 17
TBCD	ENST00000576677.6	TSL:1	n.1597C>A		non_coding_transcript_exon	Exon 6 of 16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 03, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.062

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

PhyloP100

3.6

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.25

Sift

Benign

0.031

Sift4G

Benign

0.091

Polyphen

0.58

Vest4

0.45

MutPred

0.53

Loss of MoRF binding (P = 0.0424)

MVP

0.69

MPC

0.75

ClinPred

0.90

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.27

gMVP

0.66

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over