rs28939693

Positions:

• chr18-3457441-A-G
• chr18-3457441-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003244.4(TGIF1):​c.320A>G​(p.Gln107Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: TGIF1 NM_003244.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2645986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.320A>G	p.Gln107Arg	missense_variant	3/3	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10	c.320A>G	p.Gln107Arg	missense_variant	3/3	1	NM_003244.4	ENSP00000339631.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;.;.;.;.;T;.;.;.;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.060
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	D;.;D;.;D;D;D;D;.;D;D;.;.;D;D;D;.;D;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.074	T;T;T;T;.;T;T;T;D;D;T;T;T;D;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.012	.;.;.;.;.;.;.;.;B;B;.;.;.;B;.;.;.;.;.
Vest4		0.064, 0.062, 0.075, 0.063, 0.074, 0.080, 0.094, 0.076, 0.073, 0.067
MutPred		0.31		.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.018);.;.;.;.;.;
MVP		0.86
MPC		0.40
ClinPred		0.50	T
GERP RS		4.3
Varity_R		0.23
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28939693; hg19: chr18-3457439;