rs397515503

Positions:

• chr18-3457702-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The ENST00000343820.10(TGIF1):​c.581T>G​(p.Val194Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGIF1 ENST00000343820.10 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.47

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.182237).
• BP6: Variant 18-3457702-T-G is Benign according to our data. Variant chr18-3457702-T-G is described in ClinVar as [Benign]. Clinvar id is 65507.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.581T>G	p.Val194Gly	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.581T>G	p.Val194Gly	missense_variant	3/3	1	NM_003244.4	ENSP00000339631	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Holoprosencephaly 4 Benign:1

Benign, no assertion criteria provided

curation

GeneReviews

Aug 29, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.00023	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.19	.;.;.;T;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	.;.;T;T;T;.;T;.;.;T;T;.;.
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.44	N;.;.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.13	T;.;.;D;T;T;T;T;T;D;T;T;T
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.32, 0.013	.;.;.;.;.;B;B;.;.;B;.;.;.
Vest4		0.25
MutPred		0.49		.;.;.;.;.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0098);.;.;.;
MVP		0.63
MPC		0.59
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515503; hg19: chr18-3457700;