rs143886167

Positions:

• chr1-235414500-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003193.5(TBCE):​c.253A>G​(p.Ile85Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,613,842 control chromosomes in the GnomAD database, including 4 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.327

Genes affected

TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E 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. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004742801).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000716 (109/152198) while in subpopulation NFE AF= 0.00075 (51/68024). AF 95% confidence interval is 0.000586. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBCE	NM_003193.5	c.253A>G	p.Ile85Val	missense_variant	4/17	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.253A>G	p.Ile85Val	missense_variant	4/18		NP_001274730.1
TBCE	NM_001079515.3	c.253A>G	p.Ile85Val	missense_variant	4/17		NP_001072983.1
TBCE	NM_001287802.2	c.-143A>G		5_prime_UTR_variant	3/16		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2	c.253A>G	p.Ile85Val	missense_variant	4/17		NM_003193.5	ENSP00000494796	P1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000872 AC: 219 AN: 251150 Hom.: 0 AF XY: 0.000942 AC XY: 128 AN XY: 135832

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.000758

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000640 AC: 936 AN: 1461644 Hom.: 4 Cov.: 31 AF XY: 0.000638 AC XY: 464 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00526

Gnomad4 NFE exome AF: 0.000547

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000888 AC XY: 66 AN XY: 74360

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000659 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000931 AC: 113

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Hypoparathyroidism-retardation-dysmorphism syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

TBCE-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.10
DANN	Benign	0.42
DEOGEN2	Benign	0.086	T;T;T;T;T;.;T;T;T;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.60	.;.;.;.;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0047	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N;N;N;N;N;.;N;N;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.48	.;.;.;.;.;.;.;.;N;.;N;N;.
REVEL	Benign	0.033
Sift	Benign	0.59	.;.;.;.;.;.;.;.;T;.;T;T;.
Sift4G	Benign	0.93	.;.;.;.;.;.;.;.;T;.;T;T;.
Polyphen		0.0	B;B;B;B;B;.;B;B;B;.;.;.;.
Vest4		0.15, 0.17, 0.16
MVP		0.21
MPC		0.18
ClinPred		0.0083	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143886167; hg19: chr1-235577815;