18-3451541-GA-G

Variant names:

• chr18-3451541-GA-G
• rs150513143
• NM_003244.4:c.16+1037delA

Variant summary

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

The NM_003244.4(TGIF1):​c.16+1037delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 1,008,350 control chromosomes in the GnomAD database, including 4,204 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.074 (443 hom., cov: 31)
  • Exomes 𝑓: 0.093 (3761 hom.)
• Consequence: TGIF1 NM_003244.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.211

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 18-3451541-GA-G is Benign according to our data. Variant chr18-3451541-GA-G is described in ClinVar as [Benign]. Clinvar id is 674962.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.16+1037delA		intron_variant	Intron 1 of 2	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10	c.16+1037delA		intron_variant	Intron 1 of 2	1	NM_003244.4	ENSP00000339631.6

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11325 AN: 152150 Hom.: 440 Cov.: 31

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0656

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.0755

GnomAD4 exome AF: 0.0926 AC: 79256 AN: 856082 Hom.: 3761 Cov.: 7 AF XY: 0.0925 AC XY: 36655 AN XY: 396266

Gnomad4 AFR exome AF: 0.0524

Gnomad4 AMR exome AF: 0.0353

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.0782

Gnomad4 FIN exome AF: 0.0481

Gnomad4 NFE exome AF: 0.0942

Gnomad4 OTH exome AF: 0.0934

GnomAD4 genome AF: 0.0745 AC: 11338 AN: 152268 Hom.: 443 Cov.: 31 AF XY: 0.0719 AC XY: 5355 AN XY: 74474

Gnomad4 AFR AF: 0.0576

Gnomad4 AMR AF: 0.0655

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.0766

Gnomad4 FIN AF: 0.0518

Gnomad4 NFE AF: 0.0904

Gnomad4 OTH AF: 0.0790

Bravo AF: 0.0740

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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: rs150513143; hg19: chr18-3451539;