NM_005993.5:c.2859T>C

Variant names:

• chr17-82929368-T-C
• rs1127986
• NM_005993.5:c.2859T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005993.5(TBCD):​c.2859T>C​(p.Asp953Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,612,410 control chromosomes in the GnomAD database, including 50,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4698 hom., cov: 34)
  • Exomes 𝑓: 0.25 (46140 hom.)
• Consequence: TBCD NM_005993.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.54
• Publications: 21 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-82929368-T-C is Benign according to our data. Variant chr17-82929368-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

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.2859T>C	p.Asp953Asp	synonymous	Exon 32 of 39	NP_005984.3
	TBCD	NM_001411101.1		c.2808T>C	p.Asp936Asp	synonymous	Exon 31 of 38	NP_001398030.1
	TBCD	NM_001411102.1		c.2778T>C	p.Asp926Asp	synonymous	Exon 31 of 38	NP_001398031.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCD	ENST00000355528.9	TSL:1 MANE Select	c.2859T>C	p.Asp953Asp	synonymous	Exon 32 of 39	ENSP00000347719.4
	TBCD	ENST00000571796.5	TSL:1	n.1517T>C		non_coding_transcript_exon	Exon 17 of 17
	TBCD	ENST00000576677.6	TSL:1	n.1988T>C		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37819 AN: 152070 Hom.: 4693 Cov.: 34

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.253 AC: 62652 AN: 248076 AF XY: 0.252

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.250 AC: 365007 AN: 1460220 Hom.: 46140 Cov.: 72 AF XY: 0.250 AC XY: 181425 AN XY: 726268

African (AFR) AF: 0.238 AC: 7949 AN: 33466

American (AMR) AF: 0.287 AC: 12826 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6919 AN: 26124

East Asian (EAS) AF: 0.160 AC: 6350 AN: 39682

South Asian (SAS) AF: 0.252 AC: 21727 AN: 86236

European-Finnish (FIN) AF: 0.273 AC: 14358 AN: 52640

Middle Eastern (MID) AF: 0.265 AC: 1528 AN: 5766

European-Non Finnish (NFE) AF: 0.250 AC: 278012 AN: 1111294

Other (OTH) AF: 0.254 AC: 15338 AN: 60332

GnomAD4 genome AF: 0.249 AC: 37839 AN: 152190 Hom.: 4698 Cov.: 34 AF XY: 0.250 AC XY: 18578 AN XY: 74388

African (AFR) AF: 0.238 AC: 9888 AN: 41540

American (AMR) AF: 0.281 AC: 4297 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 915 AN: 3470

East Asian (EAS) AF: 0.204 AC: 1053 AN: 5168

South Asian (SAS) AF: 0.261 AC: 1258 AN: 4812

European-Finnish (FIN) AF: 0.275 AC: 2912 AN: 10592

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16813 AN: 67992

Other (OTH) AF: 0.254 AC: 537 AN: 2116

Alfa AF: 0.246 Hom.: 8512

Bravo AF: 0.249

Asia WGS AF: 0.245 AC: 852 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.261

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.025
DANN	Benign	0.35
PhyloP100		-1.5
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1127986; hg19: chr17-80887244; COSMIC: COSV62801180; COSMIC: COSV62801180;