chr18-3451632-G-C

Variant names:

• chr18-3451632-G-C
• rs539858187
• NM_003244.4:c.16+1127G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_170695.5(TGIF1):​c.-795G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,110,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: TGIF1 NM_170695.5 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.50
• Publications: 0 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, Laboratory for Molecular Medicine, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000302876 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-3451632-G-C is Benign according to our data. Variant chr18-3451632-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3047528.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 123 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170695.5. 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.16+1127G>C		intron	N/A	NP_003235.1	Q15583-2
	TGIF1	NM_001374397.1		c.-184G>C		5_prime_UTR	Exon 1 of 3	NP_001361326.1	Q15583-4
	TGIF1	NM_170695.5		c.-795G>C		5_prime_UTR	Exon 1 of 3	NP_733796.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGIF1	ENST00000343820.10	TSL:1 MANE Select	c.16+1127G>C		intron	N/A	ENSP00000339631.6	Q15583-2
	TGIF1	ENST00000551541.5	TSL:2	c.-188G>C		5_prime_UTR	Exon 1 of 3	ENSP00000450025.1	Q15583-4
	TGIF1	ENST00000618001.4	TSL:2	c.58+3835G>C		intron	N/A	ENSP00000483499.1	Q15583-3

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00177 AC: 1696 AN: 958020 Hom.: 0 Cov.: 29 AF XY: 0.00178 AC XY: 799 AN XY: 447852

African (AFR) AF: 0.000200 AC: 4 AN: 20040

American (AMR) AF: 0.000187 AC: 1 AN: 5350

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 13 AN: 10268

East Asian (EAS) AF: 0.000202 AC: 3 AN: 14852

South Asian (SAS) AF: 0.0000538 AC: 1 AN: 18604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7486

Middle Eastern (MID) AF: 0.000861 AC: 2 AN: 2322

European-Non Finnish (NFE) AF: 0.00193 AC: 1623 AN: 843038

Other (OTH) AF: 0.00136 AC: 49 AN: 36060

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74514

African (AFR) AF: 0.000265 AC: 11 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000945

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TGIF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		1.5
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs539858187; hg19: chr18-3451630; COSMIC: COSV107364528;