1-235437356-G-C

Position:

chr1-235437356-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003193.5(TBCE):c.998G>C(p.Ser333Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,614,094 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 26 hom. )

Consequence

TBCE
NM_003193.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.98

Variant links:

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]

TBCE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008432835).

BP6

Variant 1-235437356-G-C is Benign according to our data. Variant chr1-235437356-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 235262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235437356-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00939 (1429/152222) while in subpopulation AFR AF= 0.0327 (1360/41528). AF 95% confidence interval is 0.0313. There are 21 homozygotes in gnomad4. There are 667 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBCE	NM_003193.5 linkuse as main transcript	c.998G>C	p.Ser333Thr	missense_variant	12/17	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2 linkuse as main transcript	c.1151G>C	p.Ser384Thr	missense_variant	13/18		NP_001274730.1
TBCE	NM_001079515.3 linkuse as main transcript	c.998G>C	p.Ser333Thr	missense_variant	12/17		NP_001072983.1
TBCE	NM_001287802.2 linkuse as main transcript	c.659G>C	p.Ser220Thr	missense_variant	11/16		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2 linkuse as main transcript	c.998G>C	p.Ser333Thr	missense_variant	12/17		NM_003193.5	ENSP00000494796	P1	Q15813-1

Frequencies

GnomAD3 genomes

AF:

0.00939

AC:

1428

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00252

AC:

633

AN:

251494

Hom.:

AF XY:

0.00170

AC XY:

231

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0342

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000995

AC:

1454

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

634

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0354

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00939

AC:

1429

AN:

152222

Hom.:

Cov.:

AF XY:

0.00896

AC XY:

667

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0327

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.0112

ESP6500AA

AF:

0.0279

AC:

123

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00307

AC:

373

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypoparathyroidism-retardation-dysmorphism syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.13

.;T;T;T;T;T;.;T;T;T;.;.;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.69

.;.;.;.;.;.;.;.;.;.;T;T;T;T;T

MetaRNN

Benign

0.0084

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

.;M;M;M;M;M;.;M;M;M;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

.;.;.;.;.;.;.;.;.;N;.;.;N;.;.

REVEL

Benign

0.061

Sift

Benign

0.13

.;.;.;.;.;.;.;.;.;T;.;.;T;.;.

Sift4G

Benign

0.53

.;.;.;.;.;.;.;.;.;T;.;.;T;.;.

Polyphen

0.26

.;B;B;B;B;B;.;B;B;B;.;.;.;.;.

Vest4

0.33, 0.44

MVP

0.33

MPC

0.38

ClinPred

0.024

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over