18-3457609-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163S) has been classified 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

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

holoprosencephaly 4
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

TGIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TGIF1	NM_003244.4 link	c.488C>T	p.Pro163Leu	missense_variant	Exon 3 of 3	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10 link	c.488C>T	p.Pro163Leu	missense_variant	Exon 3 of 3	1	NM_003244.4	ENSP00000339631.6

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

GnomAD2 exomes

AF:

0.0622

AC:

15635

AN:

251402

AF XY:

0.0660

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 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

African (AFR)

AF:

0.00983

AC:

329

AN:

33480

American (AMR)

AF:

0.0308

AC:

1377

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0463

AC:

1209

AN:

26136

East Asian (EAS)

AF:

0.134

AC:

5334

AN:

39698

South Asian (SAS)

AF:

0.112

AC:

9630

AN:

86256

European-Finnish (FIN)

AF:

0.0376

AC:

2008

AN:

53416

Middle Eastern (MID)

AF:

0.0943

AC:

544

AN:

5768

European-Non Finnish (NFE)

AF:

0.0569

AC:

63302

AN:

1112000

Other (OTH)

AF:

0.0668

AC:

4037

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5879

11758

17637

23516

29395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2438

4876

7314

9752

12190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0467

AC:

7111

AN:

152288

Hom.:

269

Cov.:

AF XY:

0.0473

AC XY:

3520

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0108

AC:

448

AN:

41576

American (AMR)

AF:

0.0414

AC:

633

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0429

AC:

149

AN:

3470

East Asian (EAS)

AF:

0.161

AC:

832

AN:

5174

South Asian (SAS)

AF:

0.112

AC:

540

AN:

4832

European-Finnish (FIN)

AF:

0.0361

AC:

383

AN:

10606

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0574

AC:

3904

AN:

68012

Other (OTH)

AF:

0.0558

AC:

118

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

336

671

1007

1342

1678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0532

Hom.:

825

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24215395)

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Holoprosencephaly sequence

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0

.;.;.;.;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

Benign

0.0

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

PhyloP100

7.5

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

Vest4

0.0

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

Mutation Taster

=47/53

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over