chr18-3448073-C-CG

Variant names:

• chr18-3448073-C-CG
• rs34135793
• NM_173207.4:c.58+284dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_173207.4(TGIF1):​c.58+284dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 947,416 control chromosomes in the GnomAD database, including 1,841 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (1221 hom., cov: 29)
  • Exomes 𝑓: 0.022 (620 hom.)
• Consequence: TGIF1 NM_173207.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53
• 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 -10 ACMG points.

• BP6: Variant 18-3448073-C-CG is Benign according to our data. Variant chr18-3448073-C-CG is described in ClinVar as Benign. ClinVar VariationId is 1288921.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.249 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.58+284dupG		intron	N/A	NP_775299.1	Q15583-3
	TGIF1	NM_001278686.3		c.-44-8273dupG		intron	N/A	NP_001265615.1	Q15583-4
	TGIF1	NM_174886.3		c.-44-8273dupG		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.58+284dupG		intron	N/A	ENSP00000483499.1	Q15583-3
	TGIF1	ENST00000401449.5	TSL:2	c.-44-8273dupG		intron	N/A	ENSP00000385206.1	Q15583-4
	TGIF1	ENST00000548489.6	TSL:3	c.-44-8273dupG		intron	N/A	ENSP00000447747.2	Q15583-4

Frequencies

GnomAD3 genomes AF: 0.0840 AC: 11863 AN: 141240 Hom.: 1214 Cov.: 29

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0479

Gnomad ASJ AF: 0.0751

Gnomad EAS AF: 0.00569

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.00374

Gnomad MID AF: 0.0882

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0777

GnomAD4 exome AF: 0.0219 AC: 17661 AN: 806052 Hom.: 620 Cov.: 29 AF XY: 0.0217 AC XY: 8104 AN XY: 372670

African (AFR) AF: 0.266 AC: 4103 AN: 15442

American (AMR) AF: 0.0278 AC: 26 AN: 934

Ashkenazi Jewish (ASJ) AF: 0.0765 AC: 382 AN: 4992

East Asian (EAS) AF: 0.00490 AC: 17 AN: 3468

South Asian (SAS) AF: 0.0176 AC: 278 AN: 15802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 272

Middle Eastern (MID) AF: 0.0461 AC: 72 AN: 1562

European-Non Finnish (NFE) AF: 0.0162 AC: 11929 AN: 737186

Other (OTH) AF: 0.0324 AC: 854 AN: 26394

GnomAD4 genome AF: 0.0842 AC: 11900 AN: 141364 Hom.: 1221 Cov.: 29 AF XY: 0.0812 AC XY: 5560 AN XY: 68492

African (AFR) AF: 0.254 AC: 9555 AN: 37678

American (AMR) AF: 0.0477 AC: 669 AN: 14012

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 253 AN: 3368

East Asian (EAS) AF: 0.00570 AC: 26 AN: 4558

South Asian (SAS) AF: 0.0278 AC: 113 AN: 4068

European-Finnish (FIN) AF: 0.00374 AC: 35 AN: 9348

Middle Eastern (MID) AF: 0.0915 AC: 26 AN: 284

European-Non Finnish (NFE) AF: 0.0163 AC: 1065 AN: 65232

Other (OTH) AF: 0.0815 AC: 158 AN: 1938

Alfa AF: 0.00328 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
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: rs34135793; hg19: chr18-3448071;