18-3457609-C-T

Position:

chr18-3457609-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.488C>T(p.Pro163Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0588 in 1,614,160 control chromosomes in the GnomAD database, including 3,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 269 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3145 hom. )

Consequence

TGIF1
NM_003244.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.49

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=0.0017831922).

BP6

Variant 18-3457609-C-T is Benign according to our data. Variant chr18-3457609-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 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.488C>T	p.Pro163Leu	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.488C>T	p.Pro163Leu	missense_variant	3/3	1	NM_003244.4	ENSP00000339631.6		Q15583-2

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

7119

AN:

152170

Hom.:

272

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.0769

Gnomad AMR

AF:

0.0415

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0574

Gnomad OTH

AF:

0.0540

GnomAD3 exomes

AF:

0.0622

AC:

15635

AN:

251402

Hom.:

669

AF XY:

0.0660

AC XY:

8966

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0456

Gnomad EAS exome

AF:

0.161

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0373

Gnomad NFE exome

AF:

0.0574

Gnomad OTH exome

AF:

0.0590

GnomAD4 exome

AF:

0.0600

AC:

87770

AN:

1461872

Hom.:

3145

Cov.:

AF XY:

0.0617

AC XY:

44848

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00983

Gnomad4 AMR exome

AF:

0.0308

Gnomad4 ASJ exome

AF:

0.0463

Gnomad4 EAS exome

AF:

0.134

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0376

Gnomad4 NFE exome

AF:

0.0569

Gnomad4 OTH exome

AF:

0.0668

GnomAD4 genome

AF:

0.0467

AC:

7111

AN:

152288

Hom.:

269

Cov.:

AF XY:

0.0473

AC XY:

3520

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0108

Gnomad4 AMR

AF:

0.0414

Gnomad4 ASJ

AF:

0.0429

Gnomad4 EAS

AF:

0.161

Gnomad4 SAS

AF:

0.112

Gnomad4 FIN

AF:

0.0361

Gnomad4 NFE

AF:

0.0574

Gnomad4 OTH

AF:

0.0558

Alfa

AF:

0.0528

Hom.:

415

Bravo

AF:

0.0444

TwinsUK

AF:

0.0609

AC:

226

ALSPAC

AF:

0.0550

AC:

212

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0606

AC:

521

ExAC

AF:

0.0627

AC:

7610

EpiCase

AF:

0.0636

EpiControl

AF:

0.0633

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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

Likely 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

0.089

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.29

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

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

-0.86

MutationAssessor

Uncertain

2.7

.;.;.;.;.;.;.;.;.;.;M;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.7

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

REVEL

Benign

0.23

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.98, 1.0

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

Vest4

0.27, 0.27, 0.38, 0.26, 0.19, 0.43, 0.35, 0.27, 0.31

MPC

1.1

ClinPred

0.023

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.72

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