17-82929368-T-G

Variant names:

• chr17-82929368-T-G
• NM_005993.5:c.2859T>G
• TBCD p.Asp953Glu

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005993.5(TBCD):​c.2859T>G​(p.Asp953Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D953N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 0 publications found

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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059569538).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCD	NM_005993.5	MANE Select	c.2859T>G	p.Asp953Glu	missense	Exon 32 of 39	NP_005984.3
	TBCD	NM_001411101.1		c.2808T>G	p.Asp936Glu	missense	Exon 31 of 38	NP_001398030.1	A0A804HLI2
	TBCD	NM_001411102.1		c.2778T>G	p.Asp926Glu	missense	Exon 31 of 38	NP_001398031.1	A0A804HJ32

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCD	ENST00000355528.9	TSL:1 MANE Select	c.2859T>G	p.Asp953Glu	missense	Exon 32 of 39	ENSP00000347719.4	Q9BTW9-1
	TBCD	ENST00000571796.5	TSL:1	n.1517T>G		non_coding_transcript_exon	Exon 17 of 17
	TBCD	ENST00000576677.6	TSL:1	n.1988T>G		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0010
DANN	Benign	0.68
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		-1.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.028
Sift	Benign	0.62	T
Sift4G	Benign	0.43	T
PromoterAI		-0.0049	Neutral
Varity_R		0.015
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-80887244;