rs2229335

Variant names:

• chr18-3457697-C-T
• rs2229335
• NM_003244.4:c.576C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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]

TGIF1 Gene-Disease associations (from GenCC):

• holoprosencephaly 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003244.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	NM_003244.4	MANE Select	c.576C>T	p.Val192Val	synonymous	Exon 3 of 3	NP_003235.1
	TGIF1	NM_173207.4		c.618C>T	p.Val206Val	synonymous	Exon 3 of 3	NP_775299.1
	TGIF1	NM_001278682.2		c.585C>T	p.Val195Val	synonymous	Exon 3 of 3	NP_001265611.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.576C>T	p.Val192Val	synonymous	Exon 3 of 3	ENSP00000339631.6
	TGIF1	ENST00000330513.10	TSL:1	c.516C>T	p.Val172Val	synonymous	Exon 3 of 3	ENSP00000327959.6
	TGIF1	ENST00000618001.4	TSL:2	c.618C>T	p.Val206Val	synonymous	Exon 3 of 3	ENSP00000483499.1

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

GnomAD2 exomes AF: 0.0134 AC: 3370 AN: 251432 AF XY: 0.0107

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 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

African (AFR) AF: 0.133 AC: 4461 AN: 33480

American (AMR) AF: 0.0159 AC: 713 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 512 AN: 26134

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39700

South Asian (SAS) AF: 0.00205 AC: 177 AN: 86240

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53420

Middle Eastern (MID) AF: 0.0359 AC: 207 AN: 5768

European-Non Finnish (NFE) AF: 0.00291 AC: 3232 AN: 1112012

Other (OTH) AF: 0.0172 AC: 1041 AN: 60396

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

African (AFR) AF: 0.121 AC: 5041 AN: 41516

American (AMR) AF: 0.0228 AC: 349 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 68034

Other (OTH) AF: 0.0441 AC: 93 AN: 2108

Alfa AF: 0.0386 Hom.: 221

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Holoprosencephaly 4 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Holoprosencephaly sequence Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.50
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229335; hg19: chr18-3457695;