18-3447727-C-T

Variant names:

• chr18-3447727-C-T
• rs238137
• NM_173207.4:c.-13C>T

Variant summary

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

The NM_173207.4(TGIF1):​c.-13C>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 0.041 in 1,613,918 control chromosomes in the GnomAD database, including 1,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (527 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1429 hom.)
• Consequence: TGIF1 NM_173207.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.453
• Publications: 8 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=-0.71).
• BP6: Variant 18-3447727-C-T is Benign according to our data. Variant chr18-3447727-C-T is described in ClinVar as Benign. ClinVar VariationId is 675019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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.-13C>T		5_prime_UTR	Exon 1 of 3	NP_775299.1	Q15583-3
	TGIF1	NM_001278686.3		c.-44-8627C>T		intron	N/A	NP_001265615.1	Q15583-4
	TGIF1	NM_174886.3		c.-44-8627C>T		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.-13C>T		5_prime_UTR	Exon 1 of 3	ENSP00000483499.1	Q15583-3
	TGIF1	ENST00000401449.5	TSL:2	c.-44-8627C>T		intron	N/A	ENSP00000385206.1	Q15583-4
	TGIF1	ENST00000548489.6	TSL:3	c.-44-8627C>T		intron	N/A	ENSP00000447747.2	Q15583-4

Frequencies

GnomAD3 genomes AF: 0.0694 AC: 10550 AN: 152100 Hom.: 524 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0867

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0688

GnomAD2 exomes AF: 0.0482 AC: 12110 AN: 251492 AF XY: 0.0461

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.0963

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0380 AC: 55599 AN: 1461700 Hom.: 1429 Cov.: 31 AF XY: 0.0375 AC XY: 27250 AN XY: 727162

African (AFR) AF: 0.145 AC: 4861 AN: 33474

American (AMR) AF: 0.0274 AC: 1224 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 1560 AN: 26136

East Asian (EAS) AF: 0.0779 AC: 3091 AN: 39700

South Asian (SAS) AF: 0.0198 AC: 1708 AN: 86256

European-Finnish (FIN) AF: 0.0835 AC: 4459 AN: 53416

Middle Eastern (MID) AF: 0.0567 AC: 327 AN: 5766

European-Non Finnish (NFE) AF: 0.0320 AC: 35609 AN: 1111834

Other (OTH) AF: 0.0457 AC: 2760 AN: 60394

GnomAD4 genome AF: 0.0694 AC: 10563 AN: 152218 Hom.: 527 Cov.: 32 AF XY: 0.0702 AC XY: 5226 AN XY: 74414

African (AFR) AF: 0.142 AC: 5896 AN: 41530

American (AMR) AF: 0.0375 AC: 573 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3472

East Asian (EAS) AF: 0.0869 AC: 450 AN: 5178

South Asian (SAS) AF: 0.0296 AC: 143 AN: 4830

European-Finnish (FIN) AF: 0.0817 AC: 865 AN: 10592

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0333 AC: 2268 AN: 68010

Other (OTH) AF: 0.0695 AC: 147 AN: 2114

Alfa AF: 0.0753 Hom.: 267

Bravo AF: 0.0709

Asia WGS AF: 0.0500 AC: 173 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	-0.71
CADD	Benign	1.0
DANN	Benign	0.74
PhyloP100		-0.45
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs238137; hg19: chr18-3447725;