chr1-235380161-TTGTG-T

Variant names:

• chr1-235380161-TTGTG-T
• rs10524346
• NM_003193.5:c.100+62_100+65delGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003193.5(TBCE):​c.100+62_100+65delGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,124,620 control chromosomes in the GnomAD database, including 356 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.058 (274 hom., cov: 0)
  • Exomes 𝑓: 0.033 (82 hom.)
• Consequence: TBCE NM_003193.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.504
• 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-TTGTG-T is Benign according to our data. Variant chr1-235380161-TTGTG-T is described in ClinVar as Benign. ClinVar VariationId is 1601254.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0741 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+62_100+65delGTGT		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.100+62_100+65delGTGT		intron	N/A	NP_001274730.1	Q15813-2
	TBCE	NM_001079515.3		c.100+62_100+65delGTGT		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+16delTGTG		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.100+13_100+16delTGTG		intron	N/A	ENSP00000494775.1
	TBCE	ENST00000366601.8	TSL:1	c.100+13_100+16delTGTG		intron	N/A	ENSP00000355560.4	A0A2U3TZJ6

Frequencies

GnomAD3 genomes AF: 0.0584 AC: 8146 AN: 139454 Hom.: 275 Cov.: 0

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.0525

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0814

Gnomad EAS AF: 0.0808

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.0667

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.0624

GnomAD2 exomes AF: 0.0255 AC: 4495 AN: 176408 AF XY: 0.0247

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.0288

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.0437

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0317

GnomAD4 exome AF: 0.0332 AC: 32701 AN: 985044 Hom.: 82 AF XY: 0.0348 AC XY: 17544 AN XY: 504498

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

African (AFR) AF: 0.0194 AC: 484 AN: 24922

American (AMR) AF: 0.0287 AC: 1175 AN: 40980

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 906 AN: 20718

East Asian (EAS) AF: 0.0617 AC: 2051 AN: 33268

South Asian (SAS) AF: 0.0512 AC: 3747 AN: 73152

European-Finnish (FIN) AF: 0.0536 AC: 2437 AN: 45454

Middle Eastern (MID) AF: 0.0468 AC: 208 AN: 4442

European-Non Finnish (NFE) AF: 0.0287 AC: 20077 AN: 699490

Other (OTH) AF: 0.0379 AC: 1616 AN: 42618

⚠️ 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: 0.0584 AC: 8152 AN: 139576 Hom.: 274 Cov.: 0 AF XY: 0.0600 AC XY: 4020 AN XY: 66958

African (AFR) AF: 0.0492 AC: 1884 AN: 38258

American (AMR) AF: 0.0467 AC: 630 AN: 13492

Ashkenazi Jewish (ASJ) AF: 0.0814 AC: 269 AN: 3306

East Asian (EAS) AF: 0.0807 AC: 382 AN: 4732

South Asian (SAS) AF: 0.0742 AC: 302 AN: 4068

European-Finnish (FIN) AF: 0.0895 AC: 742 AN: 8288

Middle Eastern (MID) AF: 0.0755 AC: 21 AN: 278

European-Non Finnish (NFE) AF: 0.0584 AC: 3759 AN: 64378

Other (OTH) AF: 0.0616 AC: 117 AN: 1900

Alfa AF: 0.0211 Hom.: 546

ClinVar

ClinVar submissions

Significance: 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		0.50
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;