Genetic Variant NM_001278684.2:c.-457G>C (chr18-3449779-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001278684.2(TGIF1):c.-457G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 985,552 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 13 hom. )

Consequence

TGIF1
NM_001278684.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.39

Publications

0 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:

ENSG00000302876 (HGNC:):

ENSG00000302876 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 18-3449779-G-C is Benign according to our data. Variant chr18-3449779-G-C is described in ClinVar as Benign. ClinVar VariationId is 889043.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1704/152292) while in subpopulation AFR AF = 0.0388 (1613/41558). AF 95% confidence interval is 0.0372. There are 28 homozygotes in GnomAd4. There are 794 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1704 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278684.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
TGIF1	NM_001278684.2	c.-457G>C	5_prime_UTR	Exon 1 of 4	NP_001265613.1	Q15583-2
TGIF1	NM_173208.3	c.-460G>C	5_prime_UTR	Exon 1 of 4	NP_775300.1	Q15583-2
TGIF1	NM_173209.3	c.-336G>C	5_prime_UTR	Exon 1 of 3	NP_775301.1	Q15583-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGIF1	ENST00000870198.1		c.-600G>C	5_prime_UTR	Exon 1 of 4	ENSP00000540257.1
TGIF1	ENST00000405385.7	TSL:2	c.-336G>C	5_prime_UTR	Exon 1 of 3	ENSP00000384970.2	Q15583-4
TGIF1	ENST00000618001.4	TSL:2	c.58+1982G>C	intron	N/A	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1707

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0390

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00574

GnomAD4 exome

AF:

0.000856

AC:

713

AN:

833260

Hom.:

Cov.:

AF XY:

0.000863

AC XY:

332

AN XY:

384826

show subpopulations

African (AFR)

AF:

0.0371

AC:

586

AN:

15788

American (AMR)

AF:

0.00304

AC:

AN:

988

Ashkenazi Jewish (ASJ)

AF:

0.000194

AC:

AN:

5154

East Asian (EAS)

AF:

0.00

AC:

AN:

3636

South Asian (SAS)

AF:

0.0000607

AC:

AN:

16478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

282

Middle Eastern (MID)

AF:

0.00247

AC:

AN:

1622

European-Non Finnish (NFE)

AF:

0.0000853

AC:

AN:

762008

Other (OTH)

AF:

0.00194

AC:

AN:

27304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.0112

AC:

1704

AN:

152292

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

794

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0388

AC:

1613

AN:

41558

American (AMR)

AF:

0.00418

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68024

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

167

250

334

417

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:

0.00881

Hom.:

Bravo

AF:

0.0128

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

6.0

(source)

DANN

Benign

0.37

PhyloP100

1.4

PromoterAI

0.013

Neutral

(source)

Mutation Taster

=300/0

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