18-3447963-A-G

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.126-777T>C 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 0.0242 in 886,368 control chromosomes in the GnomAD database, including 1,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.059 (622 hom., cov: 30)
  • Exomes 𝑓: 0.017 (389 hom.)
• Consequence: LOC124904237 XR_007066269.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430

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=-0.56).
• BP6: Variant 18-3447963-A-G is Benign according to our data. Variant chr18-3447963-A-G is described in ClinVar as [Benign]. Clinvar id is 672771.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124904237	XR_007066269.1	n.126-777T>C		intron_variant, non_coding_transcript_variant
TGIF1	NM_001278686.3	c.-44-8391A>G		intron_variant
TGIF1	NM_173207.4	c.58+166A>G		intron_variant
TGIF1	NM_174886.3	c.-44-8391A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000401449.5	c.-44-8391A>G		intron_variant		2
TGIF1	ENST00000548489.6	c.-44-8391A>G		intron_variant		3
TGIF1	ENST00000550958.5	c.-44-8391A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8935 AN: 151466 Hom.: 617 Cov.: 30

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00774

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.00276

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0509

GnomAD4 exome AF: 0.0170 AC: 12515 AN: 734784 Hom.: 389 AF XY: 0.0164 AC XY: 5610 AN XY: 341408

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.0393

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0591 AC: 8956 AN: 151584 Hom.: 622 Cov.: 30 AF XY: 0.0603 AC XY: 4464 AN XY: 74052

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.0399

Gnomad4 FIN AF: 0.00276

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0494

Alfa AF: 0.0302 Hom.: 42

Bravo AF: 0.0662

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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	-0.56
Cadd	Benign	4.6
Dann	Benign	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80144693; hg19: chr18-3447961; COSMIC: COSV57908483; COSMIC: COSV57908483;