5-77691437-G-A

Variant names:

• chr5-77691437-G-A
• rs1000394883
• NM_004607.3:c.308C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004607.3(TBCA):​c.308C>T​(p.Ser103Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,445,760 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: 0.0000062 (0 hom.)
• Consequence: TBCA NM_004607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08
• Publications: 1 publications found

Genes affected

TBCA (HGNC:11579): (tubulin folding cofactor A) The product of this gene 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. This gene encodes chaperonin cofactor A. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ENSG00000305113 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30422866).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004607.3. 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
	TBCA	NM_004607.3	MANE Select	c.308C>T	p.Ser103Leu	missense	Exon 4 of 4	NP_004598.1	O75347-1
	TBCA	NM_001297740.2		c.221C>T	p.Ser74Leu	missense	Exon 3 of 3	NP_001284669.1	E5RIX8
	TBCA	NM_001297738.2		c.*1685C>T		3_prime_UTR	Exon 3 of 3	NP_001284667.1	O75347-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCA	ENST00000380377.9	TSL:1 MANE Select	c.308C>T	p.Ser103Leu	missense	Exon 4 of 4	ENSP00000369736.4	O75347-1
	TBCA	ENST00000518338.6	TSL:2	c.377C>T	p.Ser126Leu	missense	Exon 5 of 5	ENSP00000429793.2	E5RHG6
	TBCA	ENST00000932729.1		c.377C>T	p.Ser126Leu	missense	Exon 5 of 5	ENSP00000602788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000844 AC: 2 AN: 236924 AF XY: 0.00000782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000623 AC: 9 AN: 1445760 Hom.: 0 Cov.: 29 AF XY: 0.00000557 AC XY: 4 AN XY: 718696

African (AFR) AF: 0.00 AC: 0 AN: 32484

American (AMR) AF: 0.00 AC: 0 AN: 40402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39350

South Asian (SAS) AF: 0.00 AC: 0 AN: 81972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4444

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1108360

Other (OTH) AF: 0.00 AC: 0 AN: 59730

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000378

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	0.17
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.30
Sift	Benign	0.065	T
Sift4G	Benign	0.070	T
Polyphen		0.23	B
Vest4		0.54
MutPred		0.40		Loss of phosphorylation at S103 (P = 0.0377)
MVP		0.26
MPC		0.42
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.53
Mutation Taster		=30/70	disease causing

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: rs1000394883; hg19: chr5-76987262;