11-121053712-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001363644.2(TBCEL):c.435G>T(p.Met145Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,611,918 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (1 hom.)
• Consequence: TBCEL NM_001363644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.110

Genes affected

TBCEL (HGNC:28115): (tubulin folding cofactor E like) Predicted to enable alpha-tubulin binding activity. Predicted to be involved in microtubule cytoskeleton organization; post-chaperonin tubulin folding pathway; and tubulin complex assembly. Predicted to be located in cytoskeleton. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TBCEL-TECTA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TBCEL
• BP4: Computational evidence support a benign effect (MetaRNN=0.00575307).
• BS2: High AC in GnomAd at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCEL	NM_001363644.2	c.435G>T	p.Met145Ile	missense_variant	5/9	ENST00000683345.1
TBCEL-TECTA	NM_001378761.1	c.435G>T	p.Met145Ile	missense_variant	4/30
TBCEL	NM_001130047.3	c.435G>T	p.Met145Ile	missense_variant	4/8
TBCEL	NM_152715.5	c.435G>T	p.Met145Ile	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCEL	ENST00000683345.1	c.435G>T	p.Met145Ile	missense_variant	5/9		NM_001363644.2	P1

Frequencies

GnomAD3 genomes AF: 0.000652 AC: 99 AN: 151806 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000810

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000588 AC: 147 AN: 250186 Hom.: 1 AF XY: 0.000592 AC XY: 80 AN XY: 135240

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000805

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000744 AC: 1086 AN: 1459994 Hom.: 1 Cov.: 31 AF XY: 0.000716 AC XY: 520 AN XY: 726314

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000874

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.000658 AC: 100 AN: 151924 Hom.: 0 Cov.: 32 AF XY: 0.000660 AC XY: 49 AN XY: 74246

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000825

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000650 Hom.: 0

Bravo AF: 0.000910

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000453 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000601

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.435G>T (p.M145I) alteration is located in exon 4 (coding exon 3) of the TBCEL gene. This alteration results from a G to T substitution at nucleotide position 435, causing the methionine (M) at amino acid position 145 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.82
DEOGEN2	Benign	0.036	T;T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.74	N;N;N;.
REVEL	Benign	0.051
Sift	Benign	0.19	T;T;T;.
Sift4G	Benign	0.64	T;T;T;.
Polyphen		0.0	B;B;.;.
Vest4		0.17
MutPred		0.40		Gain of catalytic residue at L150 (P = 0.0568);Gain of catalytic residue at L150 (P = 0.0568);Gain of catalytic residue at L150 (P = 0.0568);.;
MVP		0.15
MPC		0.83
ClinPred		0.020	T
GERP RS		1.5
Varity_R		0.036
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs140003630; hg19: chr11-120924421;