18-3451390-C-CAA

Variant names:

• chr18-3451390-C-CAA
• rs141177192
• NM_003244.4:c.16+886_16+887insAA

Variant summary

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

The NM_003244.4(TGIF1):​c.16+886_16+887insAA variant causes a intron change. The variant allele was found at a frequency of 0.074 in 985,296 control chromosomes in the GnomAD database, including 4,111 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1958 hom., cov: 30)
  • Exomes 𝑓: 0.064 (2153 hom.)
• Consequence: TGIF1 NM_003244.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.76
• 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 18-3451390-C-CAA is Benign according to our data. Variant chr18-3451390-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 1245973.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003244.4. 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_003244.4	MANE Select	c.16+886_16+887insAA		intron	N/A	NP_003235.1	Q15583-2
	TGIF1	NM_173207.4		c.58+3594_58+3595insAA		intron	N/A	NP_775299.1	Q15583-3
	TGIF1	NM_001278682.2		c.25+1735_25+1736insAA		intron	N/A	NP_001265611.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.16+885_16+886insAA		intron	N/A	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000618001.4	TSL:2	c.58+3593_58+3594insAA		intron	N/A	ENSP00000483499.1	Q15583-3
	TGIF1	ENST00000407501.6	TSL:3	c.16+885_16+886insAA		intron	N/A	ENSP00000384133.2	Q15583-2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19825 AN: 152106 Hom.: 1937 Cov.: 30

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0782

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.0728

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.0636 AC: 53023 AN: 833072 Hom.: 2153 Cov.: 28 AF XY: 0.0631 AC XY: 24258 AN XY: 384702

African (AFR) AF: 0.300 AC: 4734 AN: 15782

American (AMR) AF: 0.0732 AC: 72 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 452 AN: 5152

East Asian (EAS) AF: 0.0821 AC: 298 AN: 3630

South Asian (SAS) AF: 0.0733 AC: 1206 AN: 16460

European-Finnish (FIN) AF: 0.112 AC: 31 AN: 276

Middle Eastern (MID) AF: 0.102 AC: 166 AN: 1620

European-Non Finnish (NFE) AF: 0.0578 AC: 44058 AN: 761872

Other (OTH) AF: 0.0735 AC: 2006 AN: 27296

GnomAD4 genome AF: 0.131 AC: 19880 AN: 152224 Hom.: 1958 Cov.: 30 AF XY: 0.132 AC XY: 9819 AN XY: 74448

African (AFR) AF: 0.283 AC: 11756 AN: 41514

American (AMR) AF: 0.0779 AC: 1192 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3472

East Asian (EAS) AF: 0.0812 AC: 420 AN: 5172

South Asian (SAS) AF: 0.0733 AC: 354 AN: 4828

European-Finnish (FIN) AF: 0.109 AC: 1153 AN: 10614

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0653 AC: 4442 AN: 68008

Other (OTH) AF: 0.120 AC: 253 AN: 2116

Alfa AF: 0.0314 Hom.: 22

Bravo AF: 0.134

Asia WGS AF: 0.0730 AC: 254 AN: 3478

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		3.8
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: rs141177192; hg19: chr18-3451388;