5-150374666-C-T

Position:

chr5-150374666-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371623.1(TCOF1):c.1133C>T(p.Ala378Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,613,948 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 40 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 30 hom. )

Consequence

TCOF1
NM_001371623.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0560

Variant links:

Genes affected

TCOF1 (HGNC:11654): (treacle ribosome biogenesis factor 1) This gene encodes a nucleolar protein with a LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream binding factor (UBF). Mutations in this gene have been associated with Treacher Collins syndrome, a disorder which includes abnormal craniofacial development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

TCOF1 links:

TCOF1 (HGNC:):

TCOF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040968657).

BP6

Variant 5-150374666-C-T is Benign according to our data. Variant chr5-150374666-C-T is described in ClinVar as [Benign]. Clinvar id is 352202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1641/152130) while in subpopulation AFR AF= 0.0372 (1543/41470). AF 95% confidence interval is 0.0357. There are 40 homozygotes in gnomad4. There are 737 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1641 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCOF1	NM_001371623.1 linkuse as main transcript	c.1133C>T	p.Ala378Val	missense_variant	9/27	ENST00000643257.2	NP_001358552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCOF1	ENST00000643257.2 linkuse as main transcript	c.1133C>T	p.Ala378Val	missense_variant	9/27		NM_001371623.1	ENSP00000493815.1		Q13428-3

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1643

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00283

AC:

706

AN:

249788

Hom.:

AF XY:

0.00192

AC XY:

260

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.0385

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000802

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00107

AC:

1566

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000901

AC XY:

655

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0377

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.0108

AC:

1641

AN:

152130

Hom.:

Cov.:

AF XY:

0.00991

AC XY:

737

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0372

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.0123

ESP6500AA

AF:

0.0357

AC:

157

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00352

AC:

427

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Treacher Collins syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

.;T;.;.;.;.;.;.;.;.;.;T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.78

T;T;T;T;.;D;T;T;T;T;T;.;T

MetaRNN

Benign

0.0041

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

.;L;.;.;L;.;.;L;L;L;L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

.;N;D;D;.;.;.;.;N;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

0.090

.;T;D;T;.;.;.;.;T;T;T;T;T

Sift4G

Benign

0.23

.;T;T;T;.;.;.;.;T;T;T;T;T

Polyphen

0.19, 0.16, 0.22

.;B;B;B;.;.;.;.;B;B;B;B;.

Vest4

0.13, 0.13, 0.12, 0.11, 0.13

MVP

0.42

MPC

0.17

ClinPred

0.0049

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.061

gMVP

0.024

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over