NM_173207.4:c.26C>G

Variant names:

• chr18-3447765-C-G
• rs768781633
• NM_173207.4:c.26C>G
• TGIF1 p.Ala9Gly

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173207.4(TGIF1):​c.26C>G​(p.Ala9Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGIF1 NM_173207.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• 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

ENSG00000302876 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067536116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173207.4. 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_173207.4		c.26C>G	p.Ala9Gly	missense	Exon 1 of 3	NP_775299.1	Q15583-3
	TGIF1	NM_001278686.3		c.-44-8589C>G		intron	N/A	NP_001265615.1	Q15583-4
	TGIF1	NM_174886.3		c.-44-8589C>G		intron	N/A	NP_777480.1	Q15583-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000618001.4	TSL:2	c.26C>G	p.Ala9Gly	missense	Exon 1 of 3	ENSP00000483499.1	Q15583-3
	TGIF1	ENST00000401449.5	TSL:2	c.-44-8589C>G		intron	N/A	ENSP00000385206.1	Q15583-4
	TGIF1	ENST00000548489.6	TSL:3	c.-44-8589C>G		intron	N/A	ENSP00000447747.2	Q15583-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.0
DANN	Benign	0.87
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.24
Sift4G	Benign	0.19	T
PromoterAI		0.063	Neutral

Splicing

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: rs768781633;

hg19: chr18-3447763;