18-3447873-T-C

Variant names:

• chr18-3447873-T-C
• rs151472
• NM_173207.4:c.58+76T>C

Variant summary

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

The NM_173207.4(TGIF1):​c.58+76T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,577,428 control chromosomes in the GnomAD database, including 382,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (42143 hom., cov: 29)
  • Exomes 𝑓: 0.68 (340659 hom.)
• Consequence: TGIF1 NM_173207.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.362
• Publications: 8 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

ENSG00000302876 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 18-3447873-T-C is Benign according to our data. Variant chr18-3447873-T-C is described in ClinVar as Benign. ClinVar VariationId is 674961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_173207.4	c.58+76T>C		intron_variant	Intron 1 of 2		NP_775299.1
TGIF1	NM_001278686.3	c.-44-8481T>C		intron_variant	Intron 2 of 3		NP_001265615.1
TGIF1	NM_174886.3	c.-44-8481T>C		intron_variant	Intron 2 of 3		NP_777480.1
LOC124904237	XR_007066269.1	n.126-687A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000618001.4	c.58+76T>C		intron_variant	Intron 1 of 2	2		ENSP00000483499.1
TGIF1	ENST00000401449.5	c.-44-8481T>C		intron_variant	Intron 2 of 3	2		ENSP00000385206.1
TGIF1	ENST00000548489.6	c.-44-8481T>C		intron_variant	Intron 2 of 3	3		ENSP00000447747.2

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111171 AN: 151618 Hom.: 42105 Cov.: 29

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.685 AC: 976375 AN: 1425690 Hom.: 340659 AF XY: 0.679 AC XY: 482989 AN XY: 711436

African (AFR) AF: 0.924 AC: 30283 AN: 32774

American (AMR) AF: 0.504 AC: 22433 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 17971 AN: 25944

East Asian (EAS) AF: 0.428 AC: 16916 AN: 39492

South Asian (SAS) AF: 0.480 AC: 41031 AN: 85476

European-Finnish (FIN) AF: 0.715 AC: 38151 AN: 53342

Middle Eastern (MID) AF: 0.665 AC: 3785 AN: 5694

European-Non Finnish (NFE) AF: 0.710 AC: 765863 AN: 1079198

Other (OTH) AF: 0.674 AC: 39942 AN: 59228

GnomAD4 genome AF: 0.733 AC: 111260 AN: 151738 Hom.: 42143 Cov.: 29 AF XY: 0.727 AC XY: 53906 AN XY: 74122

African (AFR) AF: 0.913 AC: 37767 AN: 41388

American (AMR) AF: 0.617 AC: 9395 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2405 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2100 AN: 5140

South Asian (SAS) AF: 0.464 AC: 2215 AN: 4770

European-Finnish (FIN) AF: 0.706 AC: 7415 AN: 10506

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47683 AN: 67926

Other (OTH) AF: 0.713 AC: 1501 AN: 2104

Alfa AF: 0.717 Hom.: 44478

Bravo AF: 0.735

Asia WGS AF: 0.423 AC: 1475 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.4
DANN	Benign	0.39
PhyloP100		0.36
PromoterAI		0.013	Neutral
Mutation Taster		=19/81	disease causing

Splicing

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

Other links and lift over

dbSNP: rs151472; hg19: chr18-3447871; COSMIC: COSV57906662; COSMIC: COSV57906662;