dbSNP rs374229521: TBCE:c.661-1115C>A (chr1-235433089-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001287801.2(TBCE):c.804C>A(p.Asn268Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N268N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TBCE
NM_001287801.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.27

Publications

0 publications found

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:

ENSG00000285053 (HGNC:):

ENSG00000285053 links:

RPS21P1 (HGNC:36401): (ribosomal protein S21 pseudogene 1)

RPS21P1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38654757).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287801.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBCE	NM_003193.5	MANE Select	c.661-1115C>A		intron	N/A	NP_003184.1	Q15813-1
TBCE	NM_001287801.2		c.804C>A	p.Asn268Lys	missense	Exon 8 of 18	NP_001274730.1	Q15813-2
TBCE	NM_001079515.3		c.661-1115C>A		intron	N/A	NP_001072983.1	Q15813-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBCE	ENST00000642610.2	MANE Select	c.661-1115C>A	intron	N/A	ENSP00000494796.1	Q15813-1
ENSG00000285053	ENST00000647186.1		c.661-1115C>A	intron	N/A	ENSP00000494775.1
TBCE	ENST00000366601.8	TSL:1	c.472-1115C>A	intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1391500

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688734

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000317

AC:

AN:

31516

American (AMR)

AF:

0.00

AC:

AN:

36458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

36330

South Asian (SAS)

AF:

0.00

AC:

AN:

77996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085160

Other (OTH)

AF:

0.00

AC:

AN:

58258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.52

(source)

DANN

Benign

0.44

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.32

M_CAP

Benign

0.0015

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.98

PhyloP100

-1.3

PROVEAN

Benign

-0.54

REVEL

Benign

0.096

Sift

Benign

0.18

Sift4G

Benign

0.076

Vest4

0.23

MutPred

0.77

Gain of MoRF binding (P = 0.0286)

MVP

0.30

ClinPred

0.11

GERP RS

-2.4

gMVP

0.20

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over