rs2020436

Variant names:

• chr18-3448764-G-A
• rs2020436
• NM_173207.4:c.58+967G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-3448764-G-A
• chr18-3448764-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173207.4(TGIF1):​c.58+967G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 135,872 control chromosomes in the GnomAD database, including 7,728 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (7728 hom., cov: 21)
• Consequence: TGIF1 NM_173207.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 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+967G>A		intron	N/A	NP_775299.1	Q15583-3
	TGIF1	NM_001278686.3		c.-44-7590G>A		intron	N/A	NP_001265615.1	Q15583-4
	TGIF1	NM_001374396.1		c.-45+225G>A		intron	N/A	NP_001361325.1	Q15583-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000618001.4	TSL:2	c.58+967G>A		intron	N/A	ENSP00000483499.1	Q15583-3
	TGIF1	ENST00000401449.5	TSL:2	c.-44-7590G>A		intron	N/A	ENSP00000385206.1	Q15583-4
	TGIF1	ENST00000548489.6	TSL:3	c.-44-7590G>A		intron	N/A	ENSP00000447747.2	Q15583-4

Frequencies

GnomAD3 genomes AF: 0.320 AC: 43386 AN: 135790 Hom.: 7696 Cov.: 21

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.336

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.314

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.320 AC: 43449 AN: 135872 Hom.: 7728 Cov.: 21 AF XY: 0.326 AC XY: 21132 AN XY: 64852

African (AFR) AF: 0.488 AC: 16674 AN: 34196

American (AMR) AF: 0.239 AC: 3166 AN: 13220

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1063 AN: 3420

East Asian (EAS) AF: 0.203 AC: 942 AN: 4630

South Asian (SAS) AF: 0.329 AC: 1404 AN: 4268

European-Finnish (FIN) AF: 0.352 AC: 2636 AN: 7494

Middle Eastern (MID) AF: 0.332 AC: 85 AN: 256

European-Non Finnish (NFE) AF: 0.256 AC: 16780 AN: 65604

Other (OTH) AF: 0.318 AC: 605 AN: 1900

Alfa AF: 0.263 Hom.: 10510

Bravo AF: 0.317

Asia WGS AF: 0.291 AC: 1002 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.0
DANN	Benign	0.80
PhyloP100		0.035
PromoterAI		-0.13	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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: rs2020436;

hg19: chr18-3448762;