rs4468717

Positions:

chr18-3457608-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003244.4(TGIF1):c.487C>T(p.Pro163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 1,614,158 control chromosomes in the GnomAD database, including 4,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 398 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4292 hom. )

Consequence

TGIF1
NM_003244.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.93

Variant links:

Genes affected

TGIF1 (HGNC:11776): (TGFB induced factor homeobox 1) The protein encoded by this gene is a member of the three-amino acid loop extension (TALE) superclass of atypical homeodomains. TALE homeobox proteins are highly conserved transcription regulators. This particular homeodomain binds to a previously characterized retinoid X receptor responsive element from the cellular retinol-binding protein II promoter. In addition to its role in inhibiting 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element, the protein is an active transcriptional co-repressor of SMAD2 and may participate in the transmission of nuclear signals during development and in the adult. Mutations in this gene are associated with holoprosencephaly type 4, which is a structural anomaly of the brain. Alternative splicing has been observed at this locus and multiple splice variants encoding distinct isoforms are described. [provided by RefSeq, Jul 2013]

TGIF1 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=0.0017593503).

BP6

Variant 18-3457608-C-T is Benign according to our data. Variant chr18-3457608-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4 linkuse as main transcript	c.487C>T	p.Pro163Ser	missense_variant	3/3	ENST00000343820.10	NP_003235.1	Q15583-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10 linkuse as main transcript	c.487C>T	p.Pro163Ser	missense_variant	3/3	1	NM_003244.4	ENSP00000339631.6		Q15583-2

Frequencies

GnomAD3 genomes

AF:

0.0595

AC:

9059

AN:

152164

Hom.:

398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.0575

Gnomad ASJ

AF:

0.0855

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0773

Gnomad OTH

AF:

0.0735

GnomAD3 exomes

AF:

0.0638

AC:

16038

AN:

251396

Hom.:

689

AF XY:

0.0650

AC XY:

8831

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.0398

Gnomad ASJ exome

AF:

0.0851

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0272

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.0789

Gnomad OTH exome

AF:

0.0763

GnomAD4 exome

AF:

0.0724

AC:

105805

AN:

1461874

Hom.:

4292

Cov.:

AF XY:

0.0716

AC XY:

52080

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0136

Gnomad4 AMR exome

AF:

0.0393

Gnomad4 ASJ exome

AF:

0.0871

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.0285

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.0776

Gnomad4 OTH exome

AF:

0.0685

GnomAD4 genome

AF:

0.0594

AC:

9053

AN:

152284

Hom.:

398

Cov.:

AF XY:

0.0620

AC XY:

4620

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0137

Gnomad4 AMR

AF:

0.0574

Gnomad4 ASJ

AF:

0.0855

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.0308

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.0773

Gnomad4 OTH

AF:

0.0728

Alfa

AF:

0.0743

Hom.:

829

Bravo

AF:

0.0510

TwinsUK

AF:

0.0793

AC:

294

ALSPAC

AF:

0.0708

AC:

273

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0777

AC:

668

ExAC

AF:

0.0602

AC:

7313

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0806

EpiControl

AF:

0.0854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holoprosencephaly 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24215395) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Holoprosencephaly sequence

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.21

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

Eigen

Benign

0.15

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;.;.;D;D;D;.;D;.;.;D;D;.;.

MetaRNN

Benign

0.0018

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

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

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

N;N;.;.;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.050

T;T;T;T;D;T;T;T;T;T;T;T;T;T

Polyphen

0.64, 0.73

.;.;.;.;.;.;P;P;.;.;P;.;.;.

Vest4

0.080, 0.081, 0.15, 0.082, 0.097, 0.064, 0.15, 0.10, 0.10, 0.083, 0.094

MPC

0.59

ClinPred

0.024

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.71

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