rs8073471

Variant names:

• chr17-82939616-A-G
• rs8073471
• NM_005993.5:c.3479+140A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005993.5(TBCD):​c.3479+140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 688,292 control chromosomes in the GnomAD database, including 7,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1221 hom., cov: 32)
  • Exomes 𝑓: 0.14 (6341 hom.)
• Consequence: TBCD NM_005993.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.705
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 17-82939616-A-G is Benign according to our data. Variant chr17-82939616-A-G is described in ClinVar as Benign. ClinVar VariationId is 1278100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCD	NM_005993.5	c.3479+140A>G		intron_variant	Intron 37 of 38	ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCD	ENST00000355528.9	c.3479+140A>G		intron_variant	Intron 37 of 38	1	NM_005993.5	ENSP00000347719.4

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18459 AN: 152018 Hom.: 1222 Cov.: 32

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0880

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0779

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.144 AC: 77112 AN: 536156 Hom.: 6341 AF XY: 0.150 AC XY: 42301 AN XY: 281840

African (AFR) AF: 0.0936 AC: 1339 AN: 14310

American (AMR) AF: 0.0726 AC: 1643 AN: 22636

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 3006 AN: 15178

East Asian (EAS) AF: 0.0977 AC: 3093 AN: 31662

South Asian (SAS) AF: 0.262 AC: 13427 AN: 51172

European-Finnish (FIN) AF: 0.120 AC: 3830 AN: 31822

Middle Eastern (MID) AF: 0.255 AC: 971 AN: 3810

European-Non Finnish (NFE) AF: 0.136 AC: 45632 AN: 336376

Other (OTH) AF: 0.143 AC: 4171 AN: 29190

GnomAD4 genome AF: 0.121 AC: 18467 AN: 152136 Hom.: 1221 Cov.: 32 AF XY: 0.121 AC XY: 9030 AN XY: 74396

African (AFR) AF: 0.0952 AC: 3955 AN: 41526

American (AMR) AF: 0.0878 AC: 1343 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 698 AN: 3470

East Asian (EAS) AF: 0.0783 AC: 404 AN: 5162

South Asian (SAS) AF: 0.255 AC: 1226 AN: 4814

European-Finnish (FIN) AF: 0.117 AC: 1242 AN: 10586

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9176 AN: 67966

Other (OTH) AF: 0.128 AC: 271 AN: 2110

Alfa AF: 0.141 Hom.: 833

Bravo AF: 0.116

Asia WGS AF: 0.163 AC: 565 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.58
DANN	Benign	0.38
PhyloP100		-0.70
PromoterAI		0.0028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs8073471; hg19: chr17-80897492; COSMIC: COSV107347829; COSMIC: COSV107347829;