rs238533

chr18-3451764-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000330513.10(TGIF1):c.-663C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,250,686 control chromosomes in the GnomAD database, including 9,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2258 hom., cov: 32)
  • Exomes 𝑓: 0.10 (6826 hom.)
• Consequence: TGIF1 ENST00000330513.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0160

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 -10 ACMG points.

• BP6: Variant 18-3451764-C-T is Benign according to our data. Variant chr18-3451764-C-T is described in ClinVar as [Benign]. Clinvar id is 675145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGIF1	NM_003244.4	c.16+1259C>T		intron_variant		ENST00000343820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000343820.10	c.16+1259C>T		intron_variant		1	NM_003244.4	P1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23086 AN: 152008 Hom.: 2247 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0968

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.104 AC: 114744 AN: 1098560 Hom.: 6826 Cov.: 30 AF XY: 0.104 AC XY: 54240 AN XY: 520120

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.0887

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0666

Gnomad4 NFE exome AF: 0.0950

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.152 AC: 23127 AN: 152126 Hom.: 2258 Cov.: 32 AF XY: 0.152 AC XY: 11310 AN XY: 74386

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.0965

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.0602

Gnomad4 NFE AF: 0.0990

Gnomad4 OTH AF: 0.150

Alfa AF: 0.110 Hom.: 1458

Bravo AF: 0.158

Asia WGS AF: 0.201 AC: 700 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.0
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs238533; hg19: chr18-3451762; COSMIC: COSV57906986; COSMIC: COSV57906986;