18-3449777-G-A

Variant names:

• chr18-3449777-G-A
• rs2238538
• NM_001278684.2:c.-459G>A

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.-462G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 985,488 control chromosomes in the GnomAD database, including 8,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1216 hom., cov: 32)
  • Exomes 𝑓: 0.13 (7234 hom.)
• Consequence: TGIF1 NM_173208.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.454
• Publications: 2 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=-0.86).
• BP6: Variant 18-3449777-G-A is Benign according to our data. Variant chr18-3449777-G-A is described in ClinVar as Benign. ClinVar VariationId is 889042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 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.-459G>A		5_prime_UTR	Exon 1 of 4	NP_001265613.1	Q15583-2
	TGIF1	NM_173208.3		c.-462G>A		5_prime_UTR	Exon 1 of 4	NP_775300.1	Q15583-2
	TGIF1	NM_173209.3		c.-338G>A		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.-602G>A		5_prime_UTR	Exon 1 of 4	ENSP00000540257.1
	TGIF1	ENST00000405385.7	TSL:2	c.-338G>A		5_prime_UTR	Exon 1 of 3	ENSP00000384970.2	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.58+1980G>A		intron	N/A	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19122 AN: 152122 Hom.: 1213 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0459

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.130 AC: 108657 AN: 833252 Hom.: 7234 Cov.: 37 AF XY: 0.131 AC XY: 50424 AN XY: 384826

African (AFR) AF: 0.129 AC: 2036 AN: 15790

American (AMR) AF: 0.0668 AC: 66 AN: 988

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 785 AN: 5154

East Asian (EAS) AF: 0.0465 AC: 169 AN: 3636

South Asian (SAS) AF: 0.114 AC: 1886 AN: 16472

European-Finnish (FIN) AF: 0.161 AC: 45 AN: 280

Middle Eastern (MID) AF: 0.109 AC: 177 AN: 1622

European-Non Finnish (NFE) AF: 0.131 AC: 100171 AN: 762008

Other (OTH) AF: 0.122 AC: 3322 AN: 27302

GnomAD4 genome AF: 0.126 AC: 19145 AN: 152236 Hom.: 1216 Cov.: 32 AF XY: 0.126 AC XY: 9353 AN XY: 74426

African (AFR) AF: 0.128 AC: 5329 AN: 41548

American (AMR) AF: 0.0848 AC: 1298 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3472

East Asian (EAS) AF: 0.0457 AC: 236 AN: 5168

South Asian (SAS) AF: 0.118 AC: 569 AN: 4828

European-Finnish (FIN) AF: 0.172 AC: 1822 AN: 10610

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9103 AN: 67994

Other (OTH) AF: 0.116 AC: 246 AN: 2114

Alfa AF: 0.127 Hom.: 477

Bravo AF: 0.120

Asia WGS AF: 0.105 AC: 364 AN: 3476

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	-0.86
CADD	Benign	6.8
DANN	Benign	0.63
PhyloP100		0.45
PromoterAI		0.034	Neutral
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: rs2238538; hg19: chr18-3449775;