11-121047537-A-G

Variant names:

• chr11-121047537-A-G
• rs776567707
• NM_001363644.2:c.143A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001363644.2(TBCEL):​c.143A>G​(p.Asn48Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TBCEL NM_001363644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

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:54857): (TBCEL-TECTA readthrough) 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 active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25152898).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCEL	NM_001363644.2	c.143A>G	p.Asn48Ser	missense_variant	Exon 4 of 9	ENST00000683345.1	NP_001350573.1
TBCEL-TECTA	NM_001378761.1	c.143A>G	p.Asn48Ser	missense_variant	Exon 3 of 30		NP_001365690.1
TBCEL	NM_001130047.3	c.143A>G	p.Asn48Ser	missense_variant	Exon 3 of 8		NP_001123519.1
TBCEL	NM_152715.5	c.143A>G	p.Asn48Ser	missense_variant	Exon 3 of 8		NP_689928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCEL	ENST00000683345.1	c.143A>G	p.Asn48Ser	missense_variant	Exon 4 of 9		NM_001363644.2	ENSP00000507873.1
TBCEL-TECTA	ENST00000645041.1	c.95A>G	p.Asn32Ser	missense_variant	Exon 2 of 10			ENSP00000496315.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250084 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460164 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726378

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.0000448 AC: 2 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60278

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143A>G (p.N48S) alteration is located in exon 3 (coding exon 2) of the TBCEL gene. This alteration results from a A to G substitution at nucleotide position 143, causing the asparagine (N) at amino acid position 48 to be replaced by a serine (S). 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	0.30
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;L;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.36	N;N;N;N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;D;T;T;.
Sift4G	Benign	0.62	T;T;T;T;.
Polyphen		0.94	P;.;P;.;.
Vest4		0.34
MutPred		0.52		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;
MVP		0.46
MPC		1.4
ClinPred		0.54	D
GERP RS		5.6
Varity_R		0.094
gMVP		0.27
Mutation Taster		=73/27	polymorphism

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: rs776567707; hg19: chr11-120918246;