rs35579976

Variant names:

• chr1-235437356-G-C
• rs35579976
• NM_003193.5:c.998G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003193.5(TBCE):​c.998G>C​(p.Ser333Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,614,094 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (26 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.98
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008432835).
• BP6: Variant 1-235437356-G-C is Benign according to our data. Variant chr1-235437356-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00939 (1429/152222) while in subpopulation AFR AF = 0.0327 (1360/41528). AF 95% confidence interval is 0.0313. There are 21 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.998G>C	p.Ser333Thr	missense	Exon 12 of 17	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.1151G>C	p.Ser384Thr	missense	Exon 13 of 18	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.998G>C	p.Ser333Thr	missense	Exon 12 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.998G>C	p.Ser333Thr	missense	Exon 12 of 17	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.998G>C	p.Ser333Thr	missense	Exon 14 of 19	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.809G>C	p.Ser270Thr	missense	Exon 10 of 15	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1428 AN: 152104 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00252 AC: 633 AN: 251494 AF XY: 0.00170

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000995 AC: 1454 AN: 1461872 Hom.: 26 Cov.: 31 AF XY: 0.000872 AC XY: 634 AN XY: 727236

African (AFR) AF: 0.0354 AC: 1186 AN: 33480

American (AMR) AF: 0.00195 AC: 87 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112002

Other (OTH) AF: 0.00258 AC: 156 AN: 60394

GnomAD4 genome AF: 0.00939 AC: 1429 AN: 152222 Hom.: 21 Cov.: 32 AF XY: 0.00896 AC XY: 667 AN XY: 74434

African (AFR) AF: 0.0327 AC: 1360 AN: 41528

American (AMR) AF: 0.00288 AC: 44 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00279 Hom.: 1

Bravo AF: 0.0112

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00307 AC: 373

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hypoparathyroidism-retardation-dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.061
Sift	Benign	0.13	T
Sift4G	Benign	0.53	T
Polyphen		0.26	B
Vest4		0.33
MVP		0.33
MPC		0.38
ClinPred		0.024	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.51
Mutation Taster		=99/1	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: rs35579976; hg19: chr1-235600671;