rs755177846

Positions:

• chr17-82938132-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 268171.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBCD	NM_005993.5	c.3365C>T	p.Pro1122Leu	missense_variant	36/39	ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBCD	ENST00000355528.9	c.3365C>T	p.Pro1122Leu	missense_variant	36/39	1	NM_005993.5	ENSP00000347719	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152234 Hom.: 0 Cov.: 34

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

GnomAD3 exomes AF: 0.0000690 AC: 17 AN: 246440 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134220

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 SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459524 Hom.: 0 Cov.: 36 AF XY: 0.0000179 AC XY: 13 AN XY: 726004

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152234 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 29, 2020	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2022	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

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	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
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	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs755177846; hg19: chr17-80896008;