rs775014444

Variant names:

• chr17-82870328-G-A
• rs775014444
• NM_005993.5:c.1423G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_005993.5(TBCD):​c.1423G>A​(p.Ala475Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,130 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329619: Published functional studies demonstrate a damaging effect with reduction of protein expression in patient fibroblasts (PMID:28158450)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A475A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.26
• Publications: 7 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet

LOC124904096 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329619: Published functional studies demonstrate a damaging effect with reduction of protein expression in patient fibroblasts (PMID: 28158450); SCV004176410: Experimental studes have shown that this missense change alters TBCD gene expression (Pode-Shakked B,et al., 2017).; SCV005077171: The variant allele was found at a frequency of 1.2e-05 in 248244 control chromosomes (gnomAD). c.1423G>A has been reported in the literature in multiple individuals affected with infantile neurodegenerative disorders including Encephalopathy, Early Onset (e.g. Edvardson_2016, AlAbdi_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding ~10% of normal TBCD intracellular abundance in fibroblasts from homozygous patient fibroblasts (Edvardson_2016). PMID: 28158450 "~10% of normal TBCD intracellular abundance in fibroblasts from homozygous patient fibroblasts (Edvardson_2016)." PMID: 28158450
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 17-82870328-G-A is Pathogenic according to our data. Variant chr17-82870328-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1423G>A	p.Ala475Thr	missense	Exon 14 of 39	NP_005984.3
	TBCD	NM_001411101.1		c.1372G>A	p.Ala458Thr	missense	Exon 13 of 38	NP_001398030.1	A0A804HLI2
	TBCD	NM_001411102.1		c.1423G>A	p.Ala475Thr	missense	Exon 14 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.1423G>A	p.Ala475Thr	missense	Exon 14 of 39	ENSP00000347719.4	Q9BTW9-1
	TBCD	ENST00000684760.1		c.1423G>A	p.Ala475Thr	missense	Exon 14 of 40	ENSP00000507696.1	A0A804HJY5
	TBCD	ENST00000684349.1		c.1423G>A	p.Ala475Thr	missense	Exon 14 of 39	ENSP00000508067.1	A0A804HKT8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248244 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461130 Hom.: 0 Cov.: 37 AF XY: 0.00000825 AC XY: 6 AN XY: 726860

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111838

Other (OTH) AF: 0.0000331 AC: 2 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (7)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.60		Gain of phosphorylation at A475 (P = 0.2524)
MVP		0.82
MPC		0.93
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.51
gMVP		0.70
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs775014444; hg19: chr17-80828204; COSMIC: COSV62804420;