rs11571510

chr18-3452224-CT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000330513.10(TGIF1):c.-202del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,590,158 control chromosomes in the GnomAD database, including 123,175 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10520 hom., cov: 30)
  • Exomes 𝑓: 0.39 (112655 hom.)
• Consequence: TGIF1 ENST00000330513.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.95

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 -16 ACMG points.

• BP6: Variant 18-3452224-CT-C is Benign according to our data. Variant chr18-3452224-CT-C is described in ClinVar as [Benign]. Clinvar id is 403532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3452224-CT-C is described in Lovd as [Benign]. Variant chr18-3452224-CT-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGIF1	NM_003244.4	c.16+1720del		intron_variant		ENST00000343820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000343820.10	c.16+1720del		intron_variant		1	NM_003244.4	P1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55004 AN: 151196 Hom.: 10512 Cov.: 30

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.318 AC: 73899 AN: 232656 Hom.: 12428 AF XY: 0.325 AC XY: 41340 AN XY: 127308

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.420

Gnomad EAS exome AF: 0.0116

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.390 AC: 561642 AN: 1438844 Hom.: 112655 Cov.: 0 AF XY: 0.388 AC XY: 277717 AN XY: 715418

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.209

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.00859

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.364 AC: 55034 AN: 151314 Hom.: 10520 Cov.: 30 AF XY: 0.358 AC XY: 26444 AN XY: 73900

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.455

Gnomad4 EAS AF: 0.0157

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.379

Alfa AF: 0.00693 Hom.: 9

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 542/2178=24.88% -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs11571510; hg19: chr18-3452222; COSMIC: COSV57906818; COSMIC: COSV57906818;