chr1-235380161-TTG-T

Variant names:

• chr1-235380161-TTG-T
• rs10524346
• NM_003193.5:c.100+64_100+65delGT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_003193.5(TBCE):​c.100+64_100+65delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0462 in 1,120,498 control chromosomes in the GnomAD database, including 788 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.10 (691 hom., cov: 0)
  • Exomes 𝑓: 0.039 (97 hom.)
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.401
• 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 -9 ACMG points.

• BP6: Variant 1-235380161-TTG-T is Benign according to our data. Variant chr1-235380161-TTG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296291.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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+64_100+65delGT		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.100+64_100+65delGT		intron	N/A	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.100+64_100+65delGT		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+14delTG		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.100+13_100+14delTG		intron	N/A	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.100+13_100+14delTG		intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.100 AC: 13913 AN: 138950 Hom.: 694 Cov.: 0

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0719

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0912

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0846

GnomAD4 exome AF: 0.0386 AC: 37907 AN: 981426 Hom.: 97 AF XY: 0.0409 AC XY: 20525 AN XY: 502404

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

African (AFR) AF: 0.0108 AC: 270 AN: 24972

American (AMR) AF: 0.0373 AC: 1515 AN: 40664

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 889 AN: 20688

East Asian (EAS) AF: 0.0445 AC: 1479 AN: 33270

South Asian (SAS) AF: 0.0583 AC: 4228 AN: 72478

European-Finnish (FIN) AF: 0.0451 AC: 2049 AN: 45482

Middle Eastern (MID) AF: 0.0423 AC: 187 AN: 4420

European-Non Finnish (NFE) AF: 0.0366 AC: 25474 AN: 696904

Other (OTH) AF: 0.0427 AC: 1816 AN: 42548

⚠️ 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 AF: 0.100 AC: 13902 AN: 139072 Hom.: 691 Cov.: 0 AF XY: 0.0984 AC XY: 6564 AN XY: 66724

African (AFR) AF: 0.0362 AC: 1387 AN: 38264

American (AMR) AF: 0.114 AC: 1526 AN: 13430

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 466 AN: 3300

East Asian (EAS) AF: 0.0785 AC: 371 AN: 4724

South Asian (SAS) AF: 0.135 AC: 546 AN: 4054

European-Finnish (FIN) AF: 0.100 AC: 825 AN: 8254

Middle Eastern (MID) AF: 0.0949 AC: 26 AN: 274

European-Non Finnish (NFE) AF: 0.133 AC: 8535 AN: 64004

Other (OTH) AF: 0.0830 AC: 157 AN: 1892

Alfa AF: 0.0751 Hom.: 546

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hypoparathyroidism-retardation-dysmorphism syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs10524346; hg19: chr1-235543476;