NM_003244.4:c.581T>G

Variant names:

• chr18-3457702-T-G
• rs397515503
• NM_003244.4:c.581T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_003244.4(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. 17/22 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 NM_003244.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.47
• Publications: 1 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 65507.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	NM_003244.4	MANE Select	c.581T>G	p.Val194Gly	missense	Exon 3 of 3	NP_003235.1
	TGIF1	NM_173207.4		c.623T>G	p.Val208Gly	missense	Exon 3 of 3	NP_775299.1
	TGIF1	NM_001278682.2		c.590T>G	p.Val197Gly	missense	Exon 3 of 3	NP_001265611.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.581T>G	p.Val194Gly	missense	Exon 3 of 3	ENSP00000339631.6
	TGIF1	ENST00000330513.10	TSL:1	c.521T>G	p.Val174Gly	missense	Exon 3 of 3	ENSP00000327959.6
	TGIF1	ENST00000618001.4	TSL:2	c.623T>G	p.Val208Gly	missense	Exon 3 of 3	ENSP00000483499.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Holoprosencephaly 4 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.25
Sift	Benign	0.13	T
Sift4G	Uncertain	0.021	D
Polyphen		0.32	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
Mutation Taster		=74/26	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: rs397515503; hg19: chr18-3457700;