rs911971278

Variant names:

• chr17-82752369-G-A
• rs911971278
• NM_005993.5:c.176G>A

Variant summary

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

The NM_005993.5(TBCD):​c.176G>A​(p.Arg59Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000525 in 1,295,258 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: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.19
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

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=0.33391076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCD	NM_005993.5	c.176G>A	p.Arg59Gln	missense_variant	Exon 1 of 39	ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCD	ENST00000355528.9	c.176G>A	p.Arg59Gln	missense_variant	Exon 1 of 39	1	NM_005993.5	ENSP00000347719.4

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151598 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000560 AC: 64 AN: 1143660 Hom.: 0 Cov.: 31 AF XY: 0.0000508 AC XY: 28 AN XY: 550892

African (AFR) AF: 0.0000441 AC: 1 AN: 22658

American (AMR) AF: 0.000242 AC: 2 AN: 8250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14778

East Asian (EAS) AF: 0.0000386 AC: 1 AN: 25904

South Asian (SAS) AF: 0.00 AC: 0 AN: 37402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3056

European-Non Finnish (NFE) AF: 0.0000604 AC: 58 AN: 959866

Other (OTH) AF: 0.0000435 AC: 2 AN: 45998

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151598 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74040

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.000197 AC: 3 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176G>A (p.R59Q) alteration is located in exon 1 (coding exon 1) of the TBCD gene. This alteration results from a G to A substitution at nucleotide position 176, causing the arginine (R) at amino acid position 59 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.
Eigen	Benign	0.062
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		1.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.19
Sift	Benign	0.31	T;.
Sift4G	Benign	0.27	T;T
Polyphen		0.96	D;.
Vest4		0.19
MutPred		0.50		Loss of MoRF binding (P = 0.2);Loss of MoRF binding (P = 0.2);
MVP		0.69
MPC		0.86
ClinPred		0.87	D
GERP RS		2.2
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.31
Mutation Taster		=83/17	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: rs911971278; hg19: chr17-80710245;