rs544793676

Variant names:

• chr1-235380083-C-T
• rs544793676
• NM_003193.5:c.34C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001287802.2(TBCE):​c.-277C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TBCE NM_001287802.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.47
• 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: Orphanet, Labcorp Genetics (formerly Invitae), 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: Ambry Genetics, ClinGen, G2P
• 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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.618
• PP5: Variant 1-235380083-C-T is Pathogenic according to our data. Variant chr1-235380083-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3581407.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287802.2. 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.34C>T	p.Arg12*	stop_gained	Exon 2 of 17	NP_003184.1	Q15813-1
	TBCE	NM_001287802.2		c.-277C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001274731.1	A0A2R8Y6Q1
	TBCE	NM_001287801.2		c.34C>T	p.Arg12*	stop_gained	Exon 2 of 18	NP_001274730.1	Q15813-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	ENST00000642610.2	MANE Select	c.34C>T	p.Arg12*	stop_gained	Exon 2 of 17	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.34C>T	p.Arg12*	stop_gained	Exon 4 of 19	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.34C>T	p.Arg12*	stop_gained	Exon 2 of 15	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461522 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive Kenny-Caffey syndrome;C1855840:Hypoparathyroidism-retardation-dysmorphism syndrome;C4310667:Encephalopathy, progressive, with amyotrophy and optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.72	D
PhyloP100		1.5
Vest4		0.79
GERP RS		2.5
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=56/144	disease causing (fs/PTC)

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: rs544793676; hg19: chr1-235543398;