18-3457778-T-G

Position:

• chr18-3457778-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003244.4(TGIF1):​c.657T>G​(p.Thr219Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,613,990 control chromosomes in the GnomAD database, including 1,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (562 hom., cov: 32)
  • Exomes 𝑓: 0.011 (642 hom.)
• Consequence: TGIF1 NM_003244.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.48

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=-1.05).
• BP6: Variant 18-3457778-T-G is Benign according to our data. Variant chr18-3457778-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 259019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.657T>G	p.Thr219Thr	synonymous_variant	3/3	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10	c.657T>G	p.Thr219Thr	synonymous_variant	3/3	1	NM_003244.4	ENSP00000339631.6

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7939 AN: 152090 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00641

Gnomad OTH AF: 0.0542

GnomAD3 exomes AF: 0.0190 AC: 4764 AN: 251380 Hom.: 265 AF XY: 0.0156 AC XY: 2120 AN XY: 135874

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.00738

Gnomad NFE exome AF: 0.00669

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0108 AC: 15737 AN: 1461782 Hom.: 642 Cov.: 31 AF XY: 0.0102 AC XY: 7389 AN XY: 727212

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.00442

Gnomad4 FIN exome AF: 0.00829

Gnomad4 NFE exome AF: 0.00549

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.0523 AC: 7967 AN: 152208 Hom.: 562 Cov.: 32 AF XY: 0.0507 AC XY: 3773 AN XY: 74432

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.00641

Gnomad4 OTH AF: 0.0536

Alfa AF: 0.0286 Hom.: 139

Bravo AF: 0.0602

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holoprosencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Holoprosencephaly sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.070
DANN	Benign	0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229336; hg19: chr18-3457776;