chr18-3457697-C-T

Position:

• chr18-3457697-C-T

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.576C>T​(p.Val192Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,138 control chromosomes in the GnomAD database, including 714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (324 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (390 hom.)
• Consequence: TGIF1 NM_003244.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.375

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=-0.85).
• BP6: Variant 18-3457697-C-T is Benign according to our data. Variant chr18-3457697-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.375 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.576C>T	p.Val192Val	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.576C>T	p.Val192Val	synonymous_variant	3/3	1	NM_003244.4	ENSP00000339631.6

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5832 AN: 152146 Hom.: 322 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.0446

GnomAD3 exomes AF: 0.0134 AC: 3370 AN: 251432 Hom.: 157 AF XY: 0.0107 AC XY: 1458 AN XY: 135890

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.00710 AC: 10382 AN: 1461874 Hom.: 390 Cov.: 31 AF XY: 0.00660 AC XY: 4798 AN XY: 727236

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00291

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0384 AC: 5843 AN: 152264 Hom.: 324 Cov.: 33 AF XY: 0.0370 AC XY: 2757 AN XY: 74452

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.0441

Alfa AF: 0.0226 Hom.: 78

Bravo AF: 0.0450

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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	-0.85
CADD	Benign	2.4
DANN	Benign	0.50
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: rs2229335; hg19: chr18-3457695;