NM_003193.5:c.100+38_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTG-T
• rs10524346
• NM_003193.5:c.100+38_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003193.5(TBCE):​c.100+38_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,138,738 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.667
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1610650.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00027 (270/998894) while in subpopulation MID AF = 0.00177 (8/4514). AF 95% confidence interval is 0.000881. There are 2 homozygotes in GnomAdExome4. There are 152 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.100+38_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.100+38_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.100+38_100+65delGTGTGTGTGTGTGTGTGTGTGTGTGTGT		intron	N/A	NP_001072983.1	Q15813-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCE	ENST00000642610.2	MANE Select	c.100+13_100+40delTGTGTGTGTGTGTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.100+13_100+40delTGTGTGTGTGTGTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.100+13_100+40delTGTGTGTGTGTGTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 20 AN: 139844 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000740

Gnomad ASJ AF: 0.000302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000201

Gnomad OTH AF: 0.000531

GnomAD4 exome AF: 0.000270 AC: 270 AN: 998894 Hom.: 2 AF XY: 0.000297 AC XY: 152 AN XY: 512066

African (AFR) AF: 0.000715 AC: 18 AN: 25162

American (AMR) AF: 0.000192 AC: 8 AN: 41600

Ashkenazi Jewish (ASJ) AF: 0.000284 AC: 6 AN: 21144

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 34036

South Asian (SAS) AF: 0.000668 AC: 50 AN: 74838

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46516

Middle Eastern (MID) AF: 0.00177 AC: 8 AN: 4514

European-Non Finnish (NFE) AF: 0.000239 AC: 169 AN: 707714

Other (OTH) AF: 0.000208 AC: 9 AN: 43370

GnomAD4 genome AF: 0.000143 AC: 20 AN: 139844 Hom.: 0 Cov.: 0 AF XY: 0.000179 AC XY: 12 AN XY: 67006

African (AFR) AF: 0.000105 AC: 4 AN: 38248

American (AMR) AF: 0.0000740 AC: 1 AN: 13508

Ashkenazi Jewish (ASJ) AF: 0.000302 AC: 1 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4758

South Asian (SAS) AF: 0.00 AC: 0 AN: 4090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.000201 AC: 13 AN: 64516

Other (OTH) AF: 0.000531 AC: 1 AN: 1882

Alfa AF: 0.00 Hom.: 546

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10524346; hg19: chr1-235543476;