rs2229337

Variant names:

• chr18-3457541-A-G
• rs2229337
• NM_003244.4:c.420A>G
• TGIF1 p.Pro140Pro

Your query was ambiguous. Multiple possible variants found:

• chr18-3457541-A-G
• chr18-3457541-A-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.420A>G​(p.Pro140Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 1,613,952 control chromosomes in the GnomAD database, including 9,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2259 hom., cov: 32)
  • Exomes 𝑓: 0.083 (7007 hom.)
• Consequence: TGIF1 NM_003244.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.40
• Publications: 14 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=-0.95).
• BP6: Variant 18-3457541-A-G is Benign according to our data. Variant chr18-3457541-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 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.420A>G	p.Pro140Pro	synonymous	Exon 3 of 3	NP_003235.1	Q15583-2
	TGIF1	NM_173207.4		c.462A>G	p.Pro154Pro	synonymous	Exon 3 of 3	NP_775299.1	Q15583-3
	TGIF1	NM_001278682.2		c.429A>G	p.Pro143Pro	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.420A>G	p.Pro140Pro	synonymous	Exon 3 of 3	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000330513.10	TSL:1	c.360A>G	p.Pro120Pro	synonymous	Exon 3 of 3	ENSP00000327959.6	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.462A>G	p.Pro154Pro	synonymous	Exon 3 of 3	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21087 AN: 151952 Hom.: 2258 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.102 AC: 25699 AN: 251440 AF XY: 0.0998

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.0483

Gnomad ASJ exome AF: 0.0879

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.0496

Gnomad NFE exome AF: 0.0690

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0826 AC: 120775 AN: 1461882 Hom.: 7007 Cov.: 31 AF XY: 0.0831 AC XY: 60402 AN XY: 727244

African (AFR) AF: 0.298 AC: 9985 AN: 33480

American (AMR) AF: 0.0530 AC: 2369 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 2386 AN: 26136

East Asian (EAS) AF: 0.267 AC: 10612 AN: 39698

South Asian (SAS) AF: 0.121 AC: 10412 AN: 86258

European-Finnish (FIN) AF: 0.0489 AC: 2613 AN: 53420

Middle Eastern (MID) AF: 0.140 AC: 809 AN: 5768

European-Non Finnish (NFE) AF: 0.0678 AC: 75394 AN: 1112006

Other (OTH) AF: 0.103 AC: 6195 AN: 60396

GnomAD4 genome AF: 0.139 AC: 21110 AN: 152070 Hom.: 2259 Cov.: 32 AF XY: 0.138 AC XY: 10235 AN XY: 74326

African (AFR) AF: 0.288 AC: 11945 AN: 41430

American (AMR) AF: 0.0801 AC: 1224 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 290 AN: 3472

East Asian (EAS) AF: 0.277 AC: 1431 AN: 5166

South Asian (SAS) AF: 0.126 AC: 607 AN: 4814

European-Finnish (FIN) AF: 0.0488 AC: 517 AN: 10586

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0691 AC: 4701 AN: 68002

Other (OTH) AF: 0.129 AC: 273 AN: 2116

Alfa AF: 0.106 Hom.: 669

Bravo AF: 0.147

Asia WGS AF: 0.190 AC: 662 AN: 3478

EpiCase AF: 0.0760

EpiControl AF: 0.0784

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	-0.95
CADD	Benign	0.035
DANN	Benign	0.19
PhyloP100		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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

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

Other links and lift over

dbSNP: rs2229337;

hg19: chr18-3457539;