rs4468717

Variant names:

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

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. P163L) has been classified as Likely benign.

• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.487C>T	p.Pro163Ser	missense_variant	Exon 3 of 3	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10	c.487C>T	p.Pro163Ser	missense_variant	Exon 3 of 3	1	NM_003244.4	ENSP00000339631.6

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

TwinsUK AF: 0.0793 AC: 294

ALSPAC AF: 0.0708 AC: 273

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.0777 AC: 668

ExAC AF: 0.0602 AC: 7313

Asia WGS AF: 0.0160 AC: 59 AN: 3478

EpiCase AF: 0.0806

EpiControl AF: 0.0854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 4 Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24215395) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holoprosencephaly sequence Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;.;.;.;.;.;T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;.;.;D;D;D;.;D;.;.;D;D;.;.
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;.;.;.;.;.;.;.;.;L;.;.;.
PhyloP100		2.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;N;.;.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D;T;.;.;D;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.050	T;T;T;T;D;T;T;T;T;T;T;T;T;T
Polyphen		0.64, 0.73	.;.;.;.;.;.;P;P;.;.;P;.;.;.
Vest4		0.080, 0.081, 0.15, 0.082, 0.097, 0.064, 0.15, 0.10, 0.10, 0.083, 0.094
MPC		0.59
ClinPred		0.024	T
GERP RS		5.3
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

Other links and lift over

dbSNP: rs4468717; hg19: chr18-3457606; COSMIC: COSV107364545;