1-235380120-G-T

Variant names:

• chr1-235380120-G-T
• rs766386026
• NM_003193.5:c.71G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003193.5(TBCE):​c.71G>T​(p.Arg24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.731
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypoparathyroidism-retardation-dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• encephalopathy, progressive, with amyotrophy and optic atrophy

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, G2P, Ambry Genetics
• autosomal recessive Kenny-Caffey syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003193.5. 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
	TBCE	NM_003193.5	MANE Select	c.71G>T	p.Arg24Leu	missense	Exon 2 of 17	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.71G>T	p.Arg24Leu	missense	Exon 2 of 18	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.71G>T	p.Arg24Leu	missense	Exon 2 of 17	NP_001072983.1	Q15813-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	ENST00000642610.2	MANE Select	c.71G>T	p.Arg24Leu	missense	Exon 2 of 17	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.71G>T	p.Arg24Leu	missense	Exon 4 of 19	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.71G>T	p.Arg24Leu	missense	Exon 2 of 15	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460426 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726516

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111032

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.73
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.41
Sift	Benign	0.11	T
Sift4G	Benign	0.073	T
Polyphen		0.74	P
Vest4		0.56
MutPred		0.74		Gain of sheet (P = 0.0043)
MVP		0.82
MPC		0.40
ClinPred		0.34	T
GERP RS		1.5
PromoterAI		-0.072	Neutral
Varity_R		0.086
gMVP		0.88
Mutation Taster		=100/0	polymorphism

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: rs766386026; hg19: chr1-235543435;