chr18-3449607-T-TGCGCC

Variant names:

• chr18-3449607-T-TGCGCC
• rs1393606991
• NM_001278682.2:c.-14_-10dupGCGCC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001278682.2(TGIF1):​c.-14_-10dupGCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 945,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TGIF1 NM_001278682.2 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.56
• 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, Laboratory for Molecular Medicine, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000302876 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 18-3449607-T-TGCGCC is Benign according to our data. Variant chr18-3449607-T-TGCGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 3032359.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278682.2. 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_001278682.2		c.-14_-10dupGCGCC		5_prime_UTR	Exon 1 of 3	NP_001265611.1
	TGIF1	NM_173207.4		c.58+1821_58+1825dupGCGCC		intron	N/A	NP_775299.1	Q15583-3
	TGIF1	NM_001278686.3		c.-44-6736_-44-6732dupGCGCC		intron	N/A	NP_001265615.1	Q15583-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000870197.1		c.-549_-545dupGCGCC		5_prime_UTR	Exon 1 of 5	ENSP00000540256.1
	TGIF1	ENST00000870198.1		c.-761_-757dupGCGCC		5_prime_UTR	Exon 1 of 4	ENSP00000540257.1
	TGIF1	ENST00000927544.1		c.-207_-203dupGCGCC		5_prime_UTR	Exon 1 of 4	ENSP00000597603.1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112686 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000313

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000497

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 19 AN: 833148 Hom.: 0 Cov.: 36 AF XY: 0.0000234 AC XY: 9 AN XY: 384746

African (AFR) AF: 0.00 AC: 0 AN: 15786

American (AMR) AF: 0.00 AC: 0 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5152

East Asian (EAS) AF: 0.00 AC: 0 AN: 3630

South Asian (SAS) AF: 0.0000607 AC: 1 AN: 16462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AF: 0.000617 AC: 1 AN: 1620

European-Non Finnish (NFE) AF: 0.0000223 AC: 17 AN: 761940

Other (OTH) AF: 0.00 AC: 0 AN: 27298

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112686 Hom.: 0 Cov.: 31 AF XY: 0.0000586 AC XY: 3 AN XY: 51234

African (AFR) AF: 0.00 AC: 0 AN: 28916

American (AMR) AF: 0.00 AC: 0 AN: 7498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3200

East Asian (EAS) AF: 0.00 AC: 0 AN: 3278

South Asian (SAS) AF: 0.000313 AC: 1 AN: 3190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.0000497 AC: 3 AN: 60402

Other (OTH) AF: 0.00 AC: 0 AN: 1538

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TGIF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1393606991; hg19: chr18-3449605;