rs4468717

Variant names:

• chr18-3457608-C-T
• rs4468717
• NM_003244.4:c.487C>T
• TGIF1 p.Pro163Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003244.4(TGIF1):​c.487C>T​(p.Pro163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 1,614,158 control chromosomes in the GnomAD database, including 4,690 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (398 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4292 hom.)
• Consequence: TGIF1 NM_003244.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.93
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017593503).
• BP6: Variant 18-3457608-C-T is Benign according to our data. Variant chr18-3457608-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	NM_003244.4	MANE Select	c.487C>T	p.Pro163Ser	missense	Exon 3 of 3	NP_003235.1	Q15583-2
	TGIF1	NM_173207.4		c.529C>T	p.Pro177Ser	missense	Exon 3 of 3	NP_775299.1	Q15583-3
	TGIF1	NM_001278682.2		c.496C>T	p.Pro166Ser	missense	Exon 3 of 3	NP_001265611.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.487C>T	p.Pro163Ser	missense	Exon 3 of 3	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000330513.10	TSL:1	c.427C>T	p.Pro143Ser	missense	Exon 3 of 3	ENSP00000327959.6	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.529C>T	p.Pro177Ser	missense	Exon 3 of 3	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9059 AN: 152164 Hom.: 398 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.0735

GnomAD2 exomes AF: 0.0638 AC: 16038 AN: 251396 AF XY: 0.0650

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0851

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.0789

Gnomad OTH exome AF: 0.0763

GnomAD4 exome AF: 0.0724 AC: 105805 AN: 1461874 Hom.: 4292 Cov.: 32 AF XY: 0.0716 AC XY: 52080 AN XY: 727236

African (AFR) AF: 0.0136 AC: 454 AN: 33480

American (AMR) AF: 0.0393 AC: 1757 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0871 AC: 2276 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0285 AC: 2459 AN: 86258

European-Finnish (FIN) AF: 0.144 AC: 7701 AN: 53418

Middle Eastern (MID) AF: 0.126 AC: 724 AN: 5766

European-Non Finnish (NFE) AF: 0.0776 AC: 86285 AN: 1112000

Other (OTH) AF: 0.0685 AC: 4136 AN: 60392

GnomAD4 genome AF: 0.0594 AC: 9053 AN: 152284 Hom.: 398 Cov.: 32 AF XY: 0.0620 AC XY: 4620 AN XY: 74466

African (AFR) AF: 0.0137 AC: 570 AN: 41572

American (AMR) AF: 0.0574 AC: 878 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 297 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.0308 AC: 149 AN: 4830

European-Finnish (FIN) AF: 0.157 AC: 1659 AN: 10590

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0773 AC: 5258 AN: 68008

Other (OTH) AF: 0.0728 AC: 154 AN: 2116

Alfa AF: 0.0699 Hom.: 1003

Bravo AF: 0.0510

Asia WGS AF: 0.0160 AC: 59 AN: 3478

EpiCase AF: 0.0806

EpiControl AF: 0.0854

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Holoprosencephaly 4 (2)
-	-	2	not provided (2)
-	-	1	Holoprosencephaly sequence (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.050	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.71
Mutation Taster		=49/51	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4468717;

hg19: chr18-3457606;

COSMIC: COSV107364545;