18-3457541-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003244.4(TGIF1):​c.420A>C​(p.Pro140Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P140P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGIF1 NM_003244.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.40
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.

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>C	p.Pro140Pro	synonymous	Exon 3 of 3	NP_003235.1	Q15583-2
	TGIF1	NM_173207.4		c.462A>C	p.Pro154Pro	synonymous	Exon 3 of 3	NP_775299.1	Q15583-3
	TGIF1	NM_001278682.2		c.429A>C	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>C	p.Pro140Pro	synonymous	Exon 3 of 3	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000330513.10	TSL:1	c.360A>C	p.Pro120Pro	synonymous	Exon 3 of 3	ENSP00000327959.6	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.462A>C	p.Pro154Pro	synonymous	Exon 3 of 3	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.029
DANN	Benign	0.20
PhyloP100		-3.4
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

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

Other links and lift over

hg19: chr18-3457539;