NM_003192.3:c.515A>G

Variant names:

• chr6-42745559-T-C
• rs1762248784
• NM_003192.3:c.515A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003192.3(TBCC):​c.515A>G​(p.Lys172Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBCC NM_003192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.476
• Publications: 0 publications found

Genes affected

TBCC (HGNC:11580): (tubulin folding cofactor C) Cofactor C 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043412298).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003192.3. 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
	TBCC	NM_003192.3	MANE Select	c.515A>G	p.Lys172Arg	missense	Exon 1 of 1	NP_003183.2	Q15814

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCC	ENST00000372876.2	TSL:6 MANE Select	c.515A>G	p.Lys172Arg	missense	Exon 1 of 1	ENSP00000361967.1	Q15814

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.64
DANN	Benign	0.62
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.48
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.079
Sift	Benign	0.50	T
Sift4G	Benign	0.52	T
Polyphen		0.0080	B
Vest4		0.054
MutPred		0.21		Loss of ubiquitination at K172 (P = 0.0047)
MVP		0.11
ClinPred		0.41	T
GERP RS		-7.3
Varity_R		0.038
gMVP		0.36
Mutation Taster		=96/4	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: rs1762248784; hg19: chr6-42713297;