chr18-3447339-T-TAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr18-3447339-T-TAAAAAAAAAAAAAAAAAAAAAAAA
• rs11421150
• NM_001278686.3:c.-44-9000_-44-8999insAAAAAAAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_174886.3(TGIF1):​c.-44-9000_-44-8999insAAAAAAAAAAAAAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000071 (0 hom., cov: 0)
• Consequence: TGIF1 NM_174886.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• Publications: 0 publications found

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)

ENSG00000302876 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174886.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	NM_001278686.3		c.-44-9000_-44-8999insAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	NP_001265615.1	Q15583-4
	TGIF1	NM_174886.3		c.-44-9000_-44-8999insAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	NP_777480.1	Q15583-4
	TGIF1	NM_173207.4		c.-401_-400insAAAAAAAAAAAAAAAAAAAAAAAA		upstream_gene	N/A	NP_775299.1	Q15583-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000401449.5	TSL:2	c.-44-9015_-44-9014insAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000385206.1	Q15583-4
	TGIF1	ENST00000548489.6	TSL:3	c.-44-9015_-44-9014insAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000447747.2	Q15583-4
	TGIF1	ENST00000552383.5	TSL:2	c.-44-9015_-44-9014insAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000449287.1	F8VWK5

Frequencies

GnomAD3 genomes AF: 0.00000706 AC: 1 AN: 141680 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000706 AC: 1 AN: 141680 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68280

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38528

American (AMR) AF: 0.00 AC: 0 AN: 14084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.00 AC: 0 AN: 4408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65204

Other (OTH) AF: 0.00 AC: 0 AN: 1948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.27

Splicing

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

Other links and lift over

dbSNP: rs11421150; hg19: chr18-3447337;