rs1677534261

Variant names:

• chr1-235380124-T-A
• rs1677534261
• NM_003193.5:c.75T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-235380124-T-A
• chr1-235380124-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003193.5(TBCE):​c.75T>A​(p.Phe25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. F25F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.587
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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.75T>A	p.Phe25Leu	missense	Exon 2 of 17	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.75T>A	p.Phe25Leu	missense	Exon 2 of 18	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.75T>A	p.Phe25Leu	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.75T>A	p.Phe25Leu	missense	Exon 2 of 17	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.75T>A	p.Phe25Leu	missense	Exon 4 of 19	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.75T>A	p.Phe25Leu	missense	Exon 2 of 15	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.095
Eigen_PC	Benign	0.0068
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.59
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.76	P
Vest4		0.75
MutPred		0.88		Loss of catalytic residue at F25 (P = 0.0154)
MVP		0.99
MPC		0.61
ClinPred		0.99	D
GERP RS		1.9
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.85
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: rs1677534261; hg19: chr1-235543439;