18-3449794-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The XR_007066269.1(LOC124904237):n.125+738C>A variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 985,588 control chromosomes in the GnomAD database, including 2,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.050 (248 hom., cov: 32)
  • Exomes 𝑓: 0.066 (1863 hom.)
• Consequence: LOC124904237 XR_007066269.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.93

Genes affected

LOC124904237 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-3449794-G-T is Benign according to our data. Variant chr18-3449794-G-T is described in ClinVar as [Benign]. Clinvar id is 889044.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124904237	XR_007066269.1	n.125+738C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000405385.7	c.-321G>T		5_prime_UTR_variant	1/3	2
TGIF1	ENST00000401449.5	c.-44-6560G>T		intron_variant		2
TGIF1	ENST00000548489.6	c.-44-6560G>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7679 AN: 152152 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.0789

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.0502

GnomAD4 exome AF: 0.0665 AC: 55398 AN: 833320 Hom.: 1863 Cov.: 36 AF XY: 0.0660 AC XY: 25405 AN XY: 384866

Gnomad4 AFR exome AF: 0.00823

Gnomad4 AMR exome AF: 0.0536

Gnomad4 ASJ exome AF: 0.0631

Gnomad4 EAS exome AF: 0.0734

Gnomad4 SAS exome AF: 0.0818

Gnomad4 FIN exome AF: 0.0490

Gnomad4 NFE exome AF: 0.0672

Gnomad4 OTH exome AF: 0.0693

GnomAD4 genome AF: 0.0504 AC: 7677 AN: 152268 Hom.: 248 Cov.: 32 AF XY: 0.0501 AC XY: 3732 AN XY: 74444

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0469

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.0786

Gnomad4 SAS AF: 0.0792

Gnomad4 FIN AF: 0.0569

Gnomad4 NFE AF: 0.0681

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0604 Hom.: 41

Bravo AF: 0.0467

Asia WGS AF: 0.0870 AC: 305 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	16
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs2238537; hg19: chr18-3449792; COSMIC: COSV57906928; COSMIC: COSV57906928;