chr18-3449794-G-T

Variant names:

• chr18-3449794-G-T
• rs2238537
• NM_001278684.2:c.-442G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173208.3(TGIF1):​c.-445G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 985,588 control chromosomes in the GnomAD database, including 2,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (248 hom., cov: 32)
  • Exomes 𝑓: 0.066 (1863 hom.)
• Consequence: TGIF1 NM_173208.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-3449794-G-T is Benign according to our data. Variant chr18-3449794-G-T is described in ClinVar as Benign. ClinVar VariationId is 889044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173208.3. 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_001278684.2		c.-442G>T		5_prime_UTR	Exon 1 of 4	NP_001265613.1	Q15583-2
	TGIF1	NM_173208.3		c.-445G>T		5_prime_UTR	Exon 1 of 4	NP_775300.1	Q15583-2
	TGIF1	NM_173209.3		c.-321G>T		5_prime_UTR	Exon 1 of 3	NP_775301.1	Q15583-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000870198.1		c.-585G>T		5_prime_UTR	Exon 1 of 4	ENSP00000540257.1
	TGIF1	ENST00000405385.7	TSL:2	c.-321G>T		5_prime_UTR	Exon 1 of 3	ENSP00000384970.2	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.58+1997G>T		intron	N/A	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7679 AN: 152152 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.0789

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.0502

GnomAD4 exome AF: 0.0665 AC: 55398 AN: 833320 Hom.: 1863 Cov.: 36 AF XY: 0.0660 AC XY: 25405 AN XY: 384866

African (AFR) AF: 0.00823 AC: 130 AN: 15790

American (AMR) AF: 0.0536 AC: 53 AN: 988

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 325 AN: 5154

East Asian (EAS) AF: 0.0734 AC: 267 AN: 3638

South Asian (SAS) AF: 0.0818 AC: 1347 AN: 16474

European-Finnish (FIN) AF: 0.0490 AC: 14 AN: 286

Middle Eastern (MID) AF: 0.0838 AC: 136 AN: 1622

European-Non Finnish (NFE) AF: 0.0672 AC: 51234 AN: 762056

Other (OTH) AF: 0.0693 AC: 1892 AN: 27312

GnomAD4 genome AF: 0.0504 AC: 7677 AN: 152268 Hom.: 248 Cov.: 32 AF XY: 0.0501 AC XY: 3732 AN XY: 74444

African (AFR) AF: 0.0119 AC: 493 AN: 41570

American (AMR) AF: 0.0469 AC: 718 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3472

East Asian (EAS) AF: 0.0786 AC: 407 AN: 5176

South Asian (SAS) AF: 0.0792 AC: 382 AN: 4822

European-Finnish (FIN) AF: 0.0569 AC: 604 AN: 10618

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0681 AC: 4627 AN: 67984

Other (OTH) AF: 0.0521 AC: 110 AN: 2112

Alfa AF: 0.0604 Hom.: 41

Bravo AF: 0.0467

Asia WGS AF: 0.0870 AC: 305 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		1.9
PromoterAI		0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs2238537; hg19: chr18-3449792; COSMIC: COSV57906928; COSMIC: COSV57906928;