18-3425213-T-C

Variant names:

• chr18-3425213-T-C
• rs8082866
• NM_001278686.3:c.-45+6998T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001278686.3(TGIF1):​c.-45+6998T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,124 control chromosomes in the GnomAD database, including 10,025 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (10025 hom., cov: 33)
• Consequence: TGIF1 NM_001278686.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 5 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ENSG00000302876 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278686.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	NM_001278686.3		c.-45+6998T>C		intron	N/A	NP_001265615.1
	TGIF1	NM_174886.3		c.-45+6998T>C		intron	N/A	NP_777480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000401449.5	TSL:2	c.-45+6998T>C		intron	N/A	ENSP00000385206.1
	TGIF1	ENST00000548489.6	TSL:3	c.-45+6998T>C		intron	N/A	ENSP00000447747.2
	TGIF1	ENST00000552383.5	TSL:2	c.-45+6998T>C		intron	N/A	ENSP00000449287.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51190 AN: 152006 Hom.: 10002 Cov.: 33

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.337 AC: 51262 AN: 152124 Hom.: 10025 Cov.: 33 AF XY: 0.339 AC XY: 25187 AN XY: 74338

African (AFR) AF: 0.540 AC: 22431 AN: 41508

American (AMR) AF: 0.308 AC: 4710 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3466

East Asian (EAS) AF: 0.326 AC: 1688 AN: 5172

South Asian (SAS) AF: 0.144 AC: 693 AN: 4824

European-Finnish (FIN) AF: 0.319 AC: 3368 AN: 10564

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.243 AC: 16499 AN: 67994

Other (OTH) AF: 0.293 AC: 619 AN: 2110

Alfa AF: 0.267 Hom.: 9305

Bravo AF: 0.349

Asia WGS AF: 0.219 AC: 764 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.74
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs8082866; hg19: chr18-3425211;