rs2229337

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003244.4(TGIF1):c.420A>G(p.Pro140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 1,613,952 control chromosomes in the GnomAD database, including 9,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2259 hom., cov: 32)

Exomes 𝑓: 0.083 ( 7007 hom. )

Consequence

TGIF1
NM_003244.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.40

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 18-3457541-A-G is Benign according to our data. Variant chr18-3457541-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.4 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGIF1	NM_003244.4 linkuse as main transcript	c.420A>G	p.Pro140=	synonymous_variant	3/3	ENST00000343820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000343820.10 linkuse as main transcript	c.420A>G	p.Pro140=	synonymous_variant	3/3	1	NM_003244.4	P1	Q15583-2

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21087

AN:

151952

Hom.:

2258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.0769

Gnomad AMR

AF:

0.0803

Gnomad ASJ

AF:

0.0835

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.0691

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.102

AC:

25699

AN:

251440

Hom.:

2075

AF XY:

0.0998

AC XY:

13567

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.292

Gnomad AMR exome

AF:

0.0483

Gnomad ASJ exome

AF:

0.0879

Gnomad EAS exome

AF:

0.287

Gnomad SAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.0496

Gnomad NFE exome

AF:

0.0690

Gnomad OTH exome

AF:

0.0868

GnomAD4 exome

AF:

0.0826

AC:

120775

AN:

1461882

Hom.:

7007

Cov.:

AF XY:

0.0831

AC XY:

60402

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.298

Gnomad4 AMR exome

AF:

0.0530

Gnomad4 ASJ exome

AF:

0.0913

Gnomad4 EAS exome

AF:

0.267

Gnomad4 SAS exome

AF:

0.121

Gnomad4 FIN exome

AF:

0.0489

Gnomad4 NFE exome

AF:

0.0678

Gnomad4 OTH exome

AF:

0.103

GnomAD4 genome

AF:

0.139

AC:

21110

AN:

152070

Hom.:

2259

Cov.:

AF XY:

0.138

AC XY:

10235

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.288

Gnomad4 AMR

AF:

0.0801

Gnomad4 ASJ

AF:

0.0835

Gnomad4 EAS

AF:

0.277

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.0488

Gnomad4 NFE

AF:

0.0691

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.106

Hom.:

669

Bravo

AF:

0.147

Asia WGS

AF:

0.190

AC:

662

AN:

3478

EpiCase

AF:

0.0760

EpiControl

AF:

0.0784

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Holoprosencephaly 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Holoprosencephaly sequence

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

Cadd

Benign

0.035

Dann

Benign

0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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