rs12457997

chr18-3415833-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174886.3(TGIF1):c.-117-2310C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,952 control chromosomes in the GnomAD database, including 26,908 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 0.57 (26908 hom., cov: 32)
• Consequence: TGIF1 NM_174886.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGIF1	NM_001278686.3	c.-117-2310C>T		intron_variant
TGIF1	NM_174886.3	c.-117-2310C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000401449.5	c.-117-2310C>T		intron_variant		2
TGIF1	ENST00000548489.6	c.-117-2310C>T		intron_variant		3
TGIF1	ENST00000550958.5	c.-117-2310C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86998 AN: 151834 Hom.: 26898 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.605

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

GnomAD4 genome AF: 0.573 AC: 87022 AN: 151952 Hom.: 26908 Cov.: 32 AF XY: 0.577 AC XY: 42821 AN XY: 74250

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.687

Gnomad4 ASJ AF: 0.695

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.648

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.607

Alfa AF: 0.651 Hom.: 66554

Bravo AF: 0.564

Asia WGS AF: 0.666 AC: 2317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	16
Dann	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12457997; hg19: chr18-3415831;