rs2229336

Variant names:

• chr18-3457778-T-G
• rs2229336
• NM_003244.4:c.657T>G
• TGIF1 p.Thr219Thr

Your query was ambiguous. Multiple possible variants found:

• chr18-3457778-T-G
• chr18-3457778-T-C

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.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
• Publications: 9 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	NM_003244.4	MANE Select	c.657T>G	p.Thr219Thr	synonymous	Exon 3 of 3	NP_003235.1	Q15583-2
	TGIF1	NM_173207.4		c.699T>G	p.Thr233Thr	synonymous	Exon 3 of 3	NP_775299.1	Q15583-3
	TGIF1	NM_001278682.2		c.666T>G	p.Thr222Thr	synonymous	Exon 3 of 3	NP_001265611.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.657T>G	p.Thr219Thr	synonymous	Exon 3 of 3	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000330513.10	TSL:1	c.597T>G	p.Thr199Thr	synonymous	Exon 3 of 3	ENSP00000327959.6	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.699T>G	p.Thr233Thr	synonymous	Exon 3 of 3	ENSP00000483499.1	Q15583-3

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

GnomAD2 exomes AF: 0.0190 AC: 4764 AN: 251380 AF XY: 0.0156

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 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

African (AFR) AF: 0.174 AC: 5835 AN: 33480

American (AMR) AF: 0.0191 AC: 856 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 542 AN: 26136

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39700

South Asian (SAS) AF: 0.00442 AC: 381 AN: 86258

European-Finnish (FIN) AF: 0.00829 AC: 442 AN: 53312

Middle Eastern (MID) AF: 0.0374 AC: 216 AN: 5768

European-Non Finnish (NFE) AF: 0.00549 AC: 6107 AN: 1112008

Other (OTH) AF: 0.0222 AC: 1339 AN: 60396

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

African (AFR) AF: 0.164 AC: 6787 AN: 41484

American (AMR) AF: 0.0279 AC: 427 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.00735 AC: 78 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00641 AC: 436 AN: 68012

Other (OTH) AF: 0.0536 AC: 113 AN: 2108

Alfa AF: 0.0298 Hom.: 192

Bravo AF: 0.0602

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Holoprosencephaly 4 (1)
-	-	1	Holoprosencephaly sequence (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.070
DANN	Benign	0.19
PhyloP100		-5.5
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2229336;

hg19: chr18-3457776;