NM_003193.5:c.100+54_100+65delGTGTGTGTGTGT

Variant names:

• chr1-235380161-TTGTGTGTGTGTG-T
• rs10524346
• NM_003193.5:c.100+54_100+65delGTGTGTGTGTGT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_003193.5(TBCE):​c.100+54_100+65delGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 997,174 control chromosomes in the GnomAD database, including 201 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 0.025 (64 hom., cov: 0)
  • Exomes 𝑓: 0.015 (201 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-235380161-TTGTGTGTGTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTGTGTGTGTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1459272.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 201 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+54_100+65delGTGTGTGTGTGT		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.100+54_100+65delGTGTGTGTGTGT		intron	N/A	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.100+54_100+65delGTGTGTGTGTGT		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+24delTGTGTGTGTGTG		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.100+13_100+24delTGTGTGTGTGTG		intron	N/A	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.100+13_100+24delTGTGTGTGTGTG		intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3526 AN: 139808 Hom.: 64 Cov.: 0

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.0130

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0200

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0229

GnomAD4 exome AF: 0.0146 AC: 14563 AN: 997174 Hom.: 201 AF XY: 0.0150 AC XY: 7663 AN XY: 511156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0161 AC: 404 AN: 25102

American (AMR) AF: 0.00924 AC: 384 AN: 41562

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 509 AN: 21072

East Asian (EAS) AF: 0.0104 AC: 355 AN: 33996

South Asian (SAS) AF: 0.0182 AC: 1361 AN: 74654

European-Finnish (FIN) AF: 0.0299 AC: 1387 AN: 46412

Middle Eastern (MID) AF: 0.0277 AC: 125 AN: 4506

European-Non Finnish (NFE) AF: 0.0133 AC: 9364 AN: 706586

Other (OTH) AF: 0.0156 AC: 674 AN: 43284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0252 AC: 3532 AN: 139930 Hom.: 64 Cov.: 0 AF XY: 0.0257 AC XY: 1726 AN XY: 67112

African (AFR) AF: 0.0246 AC: 945 AN: 38354

American (AMR) AF: 0.0188 AC: 254 AN: 13526

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 131 AN: 3314

East Asian (EAS) AF: 0.0131 AC: 62 AN: 4748

South Asian (SAS) AF: 0.0264 AC: 108 AN: 4084

European-Finnish (FIN) AF: 0.0439 AC: 366 AN: 8346

Middle Eastern (MID) AF: 0.0216 AC: 6 AN: 278

European-Non Finnish (NFE) AF: 0.0250 AC: 1615 AN: 64502

Other (OTH) AF: 0.0232 AC: 44 AN: 1900

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		=100/0	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;