1-235380108-A-G

Variant names:

• chr1-235380108-A-G
• rs1390872569
• NM_003193.5:c.59A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003193.5(TBCE):​c.59A>G​(p.His20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. H20Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.30

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]

ENSG00000285053 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11817402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 17	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 18		NP_001274730.1
TBCE	NM_001079515.3	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 17		NP_001072983.1
TBCE	NM_001287802.2	c.-252A>G		5_prime_UTR_variant	Exon 2 of 16		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2	c.59A>G	p.His20Arg	missense_variant	Exon 2 of 17		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000645655.1	c.59A>G	p.His20Arg	missense_variant	Exon 5 of 20			ENSP00000495202.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461508 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59A>G (p.H20R) alteration is located in exon 2 (coding exon 1) of the TBCE gene. This alteration results from a A to G substitution at nucleotide position 59, causing the histidine (H) at amino acid position 20 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.037
DANN	Benign	0.30
DEOGEN2	Uncertain	0.49	T;T;T;T;T;.;.;T;T;T;.;.;.;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.67	.;.;.;.;.;.;.;.;.;.;T;T;T;T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-2.1	N;N;N;N;N;.;.;N;N;N;.;.;.;.;N;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	.;.;.;.;.;.;.;.;.;N;.;.;.;.;N;N;.
REVEL	Benign	0.25
Sift	Benign	0.47	.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;T;.
Sift4G	Benign	0.44	.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;T;.
Polyphen		0.0010	B;B;B;B;B;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.18, 0.18
MutPred		0.73		Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);
MVP		0.63
MPC		0.26
ClinPred		0.041	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.55

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

Other links and lift over

dbSNP: rs1390872569; hg19: chr1-235543423;