20-36591004-G-T

Variant names:

• chr20-36591004-G-T
• rs777025924
• NM_021809.7:c.287G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021809.7(TGIF2):​c.287G>T​(p.Arg96Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000486 in 1,440,046 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: TGIF2 NM_021809.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.29
• Publications: 0 publications found

Genes affected

TGIF2 (HGNC:15764): (TGFB induced factor homeobox 2) The protein encoded by this gene is a DNA-binding homeobox protein and a transcriptional repressor, which appears to repress transcription by recruiting histone deacetylases to TGF beta-responsive genes. This gene is amplified and over-expressed in some ovarian cancers. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 1. Read-through transcription also exists between this gene and the neighboring downstream C20orf24 (chromosome 20 open reading frame 24) gene. [provided by RefSeq, Dec 2010]

TGIF2-RAB5IF (HGNC:44664): (TGIF2-RAB5IF readthrough) This locus represents naturally occurring read-through transcription between the neighboring TGIF2 (TGFB-induced factor homeobox 2) and C20orf24 (chromosome 20 open reading frame 24) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021809.7. 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
	TGIF2	NM_021809.7	MANE Select	c.287G>T	p.Arg96Leu	missense	Exon 3 of 3	NP_068581.1	Q9GZN2-1
	TGIF2	NM_001199513.2		c.287G>T	p.Arg96Leu	missense	Exon 3 of 3	NP_001186442.1	Q9GZN2-1
	TGIF2	NM_001199514.2		c.287G>T	p.Arg96Leu	missense	Exon 3 of 3	NP_001186443.1	Q9GZN2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF2	ENST00000373872.9	TSL:1 MANE Select	c.287G>T	p.Arg96Leu	missense	Exon 3 of 3	ENSP00000362979.3	Q9GZN2-1
	TGIF2-RAB5IF	ENST00000558530.1	TSL:3	c.192+12038G>T		intron	N/A	ENSP00000454021.1
	TGIF2	ENST00000373874.6	TSL:2	c.287G>T	p.Arg96Leu	missense	Exon 3 of 3	ENSP00000362981.2	Q9GZN2-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 245160 AF XY: 0.00000753

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1440046 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 712320

African (AFR) AF: 0.00 AC: 0 AN: 32936

American (AMR) AF: 0.0000231 AC: 1 AN: 43220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.00 AC: 0 AN: 39120

South Asian (SAS) AF: 0.00 AC: 0 AN: 85116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000547 AC: 6 AN: 1096168

Other (OTH) AF: 0.00 AC: 0 AN: 59278

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	0.00087	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.40		Loss of solvent accessibility (P = 0.0052)
MVP		0.91
MPC		1.3
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.90
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777025924; hg19: chr20-35219407;