rs2229334

chr18-3457610-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003244.4(TGIF1):c.489G>A(p.Pro163=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,118 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: TGIF1 NM_003244.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.88

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-3457610-G-A is Benign according to our data. Variant chr18-3457610-G-A is described in ClinVar as [Benign]. Clinvar id is 326708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1659/152230) while in subpopulation AFR AF= 0.0356 (1479/41534). AF 95% confidence interval is 0.0341. There are 24 homozygotes in gnomad4. There are 784 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1642 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGIF1	NM_003244.4	c.489G>A	p.Pro163=	synonymous_variant	3/3	ENST00000343820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000343820.10	c.489G>A	p.Pro163=	synonymous_variant	3/3	1	NM_003244.4	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1642 AN: 152112 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00352 AC: 886 AN: 251422 Hom.: 12 AF XY: 0.00279 AC XY: 379 AN XY: 135890

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00161 AC: 2357 AN: 1461888 Hom.: 30 Cov.: 31 AF XY: 0.00148 AC XY: 1078 AN XY: 727248

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.00800

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000386

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.0109 AC: 1659 AN: 152230 Hom.: 24 Cov.: 32 AF XY: 0.0105 AC XY: 784 AN XY: 74440

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00640 Hom.: 3

Bravo AF: 0.0129

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

TGIF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.27
Dann	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2229334; hg19: chr18-3457608;