rs2292971

Positions:

• chr17-82905981-T-C
• chr17-82905981-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005993.5(TBCD):​c.1850T>C​(p.Met617Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,607,640 control chromosomes in the GnomAD database, including 157,642 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (18827 hom., cov: 34)
  • Exomes 𝑓: 0.43 (138815 hom.)
• Consequence: TBCD NM_005993.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.106

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.391527E-6).
• BP6: Variant 17-82905981-T-C is Benign according to our data. Variant chr17-82905981-T-C is described in ClinVar as [Benign]. Clinvar id is 1167401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBCD	NM_005993.5	c.1850T>C	p.Met617Thr	missense_variant	20/39	ENST00000355528.9	NP_005984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBCD	ENST00000355528.9	c.1850T>C	p.Met617Thr	missense_variant	20/39	1	NM_005993.5	ENSP00000347719	P1

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73650 AN: 151994 Hom.: 18812 Cov.: 34

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.468

GnomAD3 exomes AF: 0.438 AC: 107922 AN: 246480 Hom.: 24511 AF XY: 0.443 AC XY: 59237 AN XY: 133698

Gnomad AFR exome AF: 0.662

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.538

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.446

GnomAD4 exome AF: 0.433 AC: 629770 AN: 1455528 Hom.: 138815 Cov.: 44 AF XY: 0.435 AC XY: 315065 AN XY: 723978

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.484

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.416

Gnomad4 NFE exome AF: 0.424

Gnomad4 OTH exome AF: 0.448

GnomAD4 genome AF: 0.485 AC: 73705 AN: 152112 Hom.: 18827 Cov.: 34 AF XY: 0.482 AC XY: 35822 AN XY: 74356

Gnomad4 AFR AF: 0.656

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.408

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.464

Alfa AF: 0.429 Hom.: 30701

Bravo AF: 0.491

TwinsUK AF: 0.426 AC: 1579

ALSPAC AF: 0.423 AC: 1630

ESP6500AA AF: 0.674 AC: 2857

ESP6500EA AF: 0.431 AC: 3645

ExAC AF: 0.447 AC: 54064

Asia WGS AF: 0.448 AC: 1555 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.13
DANN	Benign	0.21
DEOGEN2	Benign	0.014	T;.;.;.;T;T;.;T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.023	T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0000044	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.8	N;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.094
Sift	Benign	1.0	T;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.;.
Vest4		0.10
MPC		0.33
ClinPred		0.0024	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292971; hg19: chr17-80863857; COSMIC: COSV62797771; COSMIC: COSV62797771;