rs1553336397

Variant names:

• chr1-235414579-T-G
• rs1553336397
• NM_003193.5:c.332T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_003193.5(TBCE):​c.332T>G​(p.Val111Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBCE NM_003193.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.99
• Publications: 0 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), G2P, Orphanet
• 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, LIMITED Submitted by: Ambry Genetics, G2P
• autosomal recessive Kenny-Caffey syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 1-235414579-T-G is Pathogenic according to our data. Variant chr1-235414579-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522753.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5	c.332T>G	p.Val111Gly	missense_variant	Exon 4 of 17	ENST00000642610.2	NP_003184.1
TBCE	NM_001287801.2	c.332T>G	p.Val111Gly	missense_variant	Exon 4 of 18		NP_001274730.1
TBCE	NM_001079515.3	c.332T>G	p.Val111Gly	missense_variant	Exon 4 of 17		NP_001072983.1
TBCE	NM_001287802.2	c.-64T>G		5_prime_UTR_variant	Exon 3 of 16		NP_001274731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2	c.332T>G	p.Val111Gly	missense_variant	Exon 4 of 17		NM_003193.5	ENSP00000494796.1
ENSG00000285053	ENST00000647186.1	c.332T>G	p.Val111Gly	missense_variant	Exon 6 of 19			ENSP00000494775.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461542 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727038

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Encephalopathy, progressive, with amyotrophy and optic atrophy Pathogenic:1

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;T;T;.;T;T;T;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	.;.;.;.;.;.;.;.;.;T;T;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.4	M;M;M;M;M;.;M;M;M;.;M;.;.
PhyloP100		6.0
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.2	.;.;.;.;.;.;.;.;D;.;D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;.;D;.;D;D;.
Sift4G	Pathogenic	0.0010	.;.;.;.;.;.;.;.;D;.;D;D;.
Polyphen		0.98	D;D;D;D;D;.;D;D;D;.;.;.;.
Vest4		0.64, 0.63, 0.64
MutPred		0.60		Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);
MVP		0.84
MPC		0.86
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.42
gMVP		0.89
Mutation Taster		=84/16	disease causing (ClinVar)

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: rs1553336397; hg19: chr1-235577894;