rs28939693

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2

The NM_003244.4(TGIF1):c.320A>T(p.Gln107Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000299 in 1,614,210 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. Q107H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

TGIF1
NM_003244.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 5.98

Publications

13 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P

TGIF1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003244.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33630174).

BP6

Variant 18-3457441-A-T is Benign according to our data. Variant chr18-3457441-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 6984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 81 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.320A>T	p.Gln107Leu	missense	Exon 3 of 3	NP_003235.1	Q15583-2
TGIF1	NM_173207.4		c.362A>T	p.Gln121Leu	missense	Exon 3 of 3	NP_775299.1	Q15583-3
TGIF1	NM_001278682.2		c.329A>T	p.Gln110Leu	missense	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.320A>T	p.Gln107Leu	missense	Exon 3 of 3	ENSP00000339631.6	Q15583-2
TGIF1	ENST00000330513.10	TSL:1	c.260A>T	p.Gln87Leu	missense	Exon 3 of 3	ENSP00000327959.6	Q15583-4
TGIF1	ENST00000618001.4	TSL:2	c.362A>T	p.Gln121Leu	missense	Exon 3 of 3	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000322

AC:

AN:

251486

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000275

AC:

402

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000604

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000533

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000183

AC:

204

AN:

1112012

Other (OTH)

AF:

0.000646

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000532

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41566

American (AMR)

AF:

0.00209

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000363

Hom.:

Bravo

AF:

0.000385

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 4 (4)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.34

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.7

PhyloP100

6.0

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.75

Sift

Benign

0.042

Sift4G

Benign

0.080

Varity_R

0.45

gMVP

0.93

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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