rs238533

Variant names:

• chr18-3451764-C-T
• rs238533
• ENST00000330513.10:c.-663C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_170695.5(TGIF1):​c.-663C>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 0.11 in 1,250,686 control chromosomes in the GnomAD database, including 9,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2258 hom., cov: 32)
  • Exomes 𝑓: 0.10 (6826 hom.)
• Consequence: TGIF1 NM_170695.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160
• Publications: 14 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-3451764-C-T is Benign according to our data. Variant chr18-3451764-C-T is described in ClinVar as Benign. ClinVar VariationId is 675145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170695.5. 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.16+1259C>T		intron	N/A	NP_003235.1	Q15583-2
	TGIF1	NM_001374397.1		c.-52C>T		5_prime_UTR	Exon 1 of 3	NP_001361326.1	Q15583-4
	TGIF1	NM_170695.5		c.-663C>T		5_prime_UTR	Exon 1 of 3	NP_733796.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000330513.10	TSL:1	c.-663C>T		5_prime_UTR	Exon 1 of 3	ENSP00000327959.6	Q15583-4
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.16+1259C>T		intron	N/A	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000345133.9	TSL:3	c.-52C>T		5_prime_UTR	Exon 1 of 3	ENSP00000343969.5	Q15583-4

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23086 AN: 152008 Hom.: 2247 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0968

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.104 AC: 114744 AN: 1098560 Hom.: 6826 Cov.: 30 AF XY: 0.104 AC XY: 54240 AN XY: 520120

African (AFR) AF: 0.275 AC: 6337 AN: 23058

American (AMR) AF: 0.0887 AC: 893 AN: 10072

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 1810 AN: 14580

East Asian (EAS) AF: 0.187 AC: 5046 AN: 26982

South Asian (SAS) AF: 0.196 AC: 4454 AN: 22694

European-Finnish (FIN) AF: 0.0666 AC: 1529 AN: 22956

Middle Eastern (MID) AF: 0.184 AC: 543 AN: 2944

European-Non Finnish (NFE) AF: 0.0950 AC: 88375 AN: 930716

Other (OTH) AF: 0.129 AC: 5757 AN: 44558

GnomAD4 genome AF: 0.152 AC: 23127 AN: 152126 Hom.: 2258 Cov.: 32 AF XY: 0.152 AC XY: 11310 AN XY: 74386

African (AFR) AF: 0.272 AC: 11281 AN: 41482

American (AMR) AF: 0.0965 AC: 1475 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3472

East Asian (EAS) AF: 0.231 AC: 1185 AN: 5136

South Asian (SAS) AF: 0.198 AC: 955 AN: 4814

European-Finnish (FIN) AF: 0.0602 AC: 639 AN: 10618

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.0990 AC: 6733 AN: 67994

Other (OTH) AF: 0.150 AC: 317 AN: 2114

Alfa AF: 0.115 Hom.: 2044

Bravo AF: 0.158

Asia WGS AF: 0.201 AC: 700 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.0
DANN	Benign	0.68
PhyloP100		-0.016
PromoterAI		-0.0049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -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

dbSNP: rs238533;

hg19: chr18-3451762;

COSMIC: COSV57906986;

COSMIC: COSV57906986;