rs2238538

Variant names:

• chr18-3449777-G-A
• rs2238538
• NM_001278684.2:c.-459G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-3449777-G-A
• chr18-3449777-G-C
• chr18-3449777-G-T

Variant summary

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

The NM_173208.3(TGIF1):​c.-462G>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 0.13 in 985,488 control chromosomes in the GnomAD database, including 8,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1216 hom., cov: 32)
  • Exomes 𝑓: 0.13 (7234 hom.)
• Consequence: TGIF1 NM_173208.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.454

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=-0.86).
• BP6: Variant 18-3449777-G-A is Benign according to our data. Variant chr18-3449777-G-A is described in ClinVar as [Benign]. Clinvar id is 889042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_001278684.2	c.-459G>A		5_prime_UTR_variant	Exon 1 of 4		NP_001265613.1
TGIF1	NM_173208.3	c.-462G>A		5_prime_UTR_variant	Exon 1 of 4		NP_775300.1
TGIF1	NM_173209.3	c.-338G>A		5_prime_UTR_variant	Exon 1 of 3		NP_775301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000405385	c.-338G>A		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000384970.2
TGIF1	ENST00000618001.4	c.58+1980G>A		intron_variant	Intron 1 of 2	2		ENSP00000483499.1
TGIF1	ENST00000401449.5	c.-44-6577G>A		intron_variant	Intron 2 of 3	2		ENSP00000385206.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19122 AN: 152122 Hom.: 1213 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0459

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.130 AC: 108657 AN: 833252 Hom.: 7234 Cov.: 37 AF XY: 0.131 AC XY: 50424 AN XY: 384826

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.0668

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.0465

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.126 AC: 19145 AN: 152236 Hom.: 1216 Cov.: 32 AF XY: 0.126 AC XY: 9353 AN XY: 74426

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0848

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0457

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.116

Alfa AF: 0.135 Hom.: 284

Bravo AF: 0.120

Asia WGS AF: 0.105 AC: 364 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.8
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs2238538; hg19: chr18-3449775;