dbSNP rs2229334: TGIF1:p.Pro163Pro (chr18-3457610-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003244.4(TGIF1):c.489G>A(p.Pro163Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,118 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 30 hom. )

Consequence

TGIF1
NM_003244.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.88

Publications

1 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: PanelApp Australia, Laboratory for Molecular Medicine, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TGIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 18-3457610-G-A is Benign according to our data. Variant chr18-3457610-G-A is described in ClinVar as Benign. ClinVar VariationId is 326708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.88 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1659/152230) while in subpopulation AFR AF = 0.0356 (1479/41534). AF 95% confidence interval is 0.0341. There are 24 homozygotes in GnomAd4. There are 784 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1659 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003244.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGIF1	NM_003244.4	MANE Select	c.489G>A	p.Pro163Pro	synonymous	Exon 3 of 3	NP_003235.1	Q15583-2
TGIF1	NM_173207.4		c.531G>A	p.Pro177Pro	synonymous	Exon 3 of 3	NP_775299.1	Q15583-3
TGIF1	NM_001278682.2		c.498G>A	p.Pro166Pro	synonymous	Exon 3 of 3	NP_001265611.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.489G>A	p.Pro163Pro	synonymous	Exon 3 of 3	ENSP00000339631.6	Q15583-2
TGIF1	ENST00000330513.10	TSL:1	c.429G>A	p.Pro143Pro	synonymous	Exon 3 of 3	ENSP00000327959.6	Q15583-4
TGIF1	ENST00000618001.4	TSL:2	c.531G>A	p.Pro177Pro	synonymous	Exon 3 of 3	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1642

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0353

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00352

AC:

886

AN:

251422

AF XY:

0.00279

show subpopulations

Gnomad AFR exome

AF:

0.0382

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00784

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000660

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00161

AC:

2357

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1078

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0368

AC:

1232

AN:

33480

American (AMR)

AF:

0.00311

AC:

139

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00800

AC:

209

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000386

AC:

429

AN:

1112006

Other (OTH)

AF:

0.00401

AC:

242

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

167

334

500

667

834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0109

AC:

1659

AN:

152230

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

784

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0356

AC:

1479

AN:

41534

American (AMR)

AF:

0.00536

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000721

AC:

AN:

68008

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00660

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 4 (2)

not provided (2)

TGIF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.27

(source)

DANN

Benign

0.44

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over