rs1229949623

Variant names:

• chr17-82752200-C-A
• rs1229949623
• NM_005993.5:c.7C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-82752200-C-A
• chr17-82752200-C-G
• chr17-82752200-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005993.5(TBCD):​c.7C>A​(p.Leu3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L3L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.657
• Publications: 0 publications found

Genes affected

TBCD (HGNC:11581): (tubulin folding cofactor D) Cofactor D 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]

TBCD Gene-Disease associations (from GenCC):

• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20565951).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005993.5. 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
	TBCD	NM_005993.5	MANE Select	c.7C>A	p.Leu3Met	missense	Exon 1 of 39	NP_005984.3
	TBCD	NM_001411101.1		c.7C>A	p.Leu3Met	missense	Exon 1 of 38	NP_001398030.1	A0A804HLI2
	TBCD	NM_001411102.1		c.7C>A	p.Leu3Met	missense	Exon 1 of 38	NP_001398031.1	A0A804HJ32

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCD	ENST00000355528.9	TSL:1 MANE Select	c.7C>A	p.Leu3Met	missense	Exon 1 of 39	ENSP00000347719.4	Q9BTW9-1
	TBCD	ENST00000684760.1		c.7C>A	p.Leu3Met	missense	Exon 1 of 40	ENSP00000507696.1	A0A804HJY5
	TBCD	ENST00000684349.1		c.7C>A	p.Leu3Met	missense	Exon 1 of 39	ENSP00000508067.1	A0A804HKT8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369788 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 675702

⚠️ 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: 28064

American (AMR) AF: 0.00 AC: 0 AN: 33384

Ashkenazi Jewish (ASJ) AF: 0.0000413 AC: 1 AN: 24222

East Asian (EAS) AF: 0.00 AC: 0 AN: 31916

South Asian (SAS) AF: 0.00 AC: 0 AN: 77026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069062

Other (OTH) AF: 0.00 AC: 0 AN: 56822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.66
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.088
Sift	Benign	0.060	T
Sift4G	Benign	0.32	T
Polyphen		0.94	P
Vest4		0.16
MutPred		0.099		Gain of catalytic residue at L3 (P = 0.1076)
MVP		0.29
MPC		0.70
ClinPred		0.23	T
GERP RS		0.29
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.29

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: rs1229949623; hg19: chr17-80710076; COSMIC: COSV56181398; COSMIC: COSV56181398;