18-3450457-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003244.4(TGIF1):c.-33C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,554,452 control chromosomes in the GnomAD database, including 26,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (8088 hom., cov: 32)
  • Exomes 𝑓: 0.14 (18256 hom.)
• Consequence: TGIF1 NM_003244.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.311

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]

LOC124904237 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-3450457-C-A is Benign according to our data. Variant chr18-3450457-C-A is described in ClinVar as [Benign]. Clinvar id is 259013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGIF1	NM_003244.4	c.-33C>A		5_prime_UTR_variant	1/3	ENST00000343820.10
LOC124904237	XR_007066269.1	n.125+75G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000343820.10	c.-33C>A		5_prime_UTR_variant	1/3	1	NM_003244.4	P1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39592 AN: 151956 Hom.: 8063 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.160 AC: 25422 AN: 158684 Hom.: 3014 AF XY: 0.156 AC XY: 13108 AN XY: 84266

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.0964

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.143 AC: 200669 AN: 1402378 Hom.: 18256 Cov.: 33 AF XY: 0.143 AC XY: 98621 AN XY: 692056

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.261 AC: 39670 AN: 152074 Hom.: 8088 Cov.: 32 AF XY: 0.259 AC XY: 19285 AN XY: 74334

Gnomad4 AFR AF: 0.576

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.234

Alfa AF: 0.122 Hom.: 372

Bravo AF: 0.270

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holoprosencephaly sequence Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.1
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs238132; hg19: chr18-3450455; COSMIC: COSV57910050; COSMIC: COSV57910050;