18-3447873-T-C

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.126-687A>G 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 0.689 in 1,577,428 control chromosomes in the GnomAD database, including 382,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (42143 hom., cov: 29)
  • Exomes 𝑓: 0.68 (340659 hom.)
• Consequence: LOC124904237 XR_007066269.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.362

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=-0.59).
• BP6: Variant 18-3447873-T-C is Benign according to our data. Variant chr18-3447873-T-C is described in ClinVar as [Benign]. Clinvar id is 674961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124904237	XR_007066269.1	n.126-687A>G		intron_variant, non_coding_transcript_variant
TGIF1	NM_001278686.3	c.-44-8481T>C		intron_variant
TGIF1	NM_173207.4	c.58+76T>C		intron_variant
TGIF1	NM_174886.3	c.-44-8481T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000401449.5	c.-44-8481T>C		intron_variant		2
TGIF1	ENST00000548489.6	c.-44-8481T>C		intron_variant		3
TGIF1	ENST00000550958.5	c.-44-8481T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111171 AN: 151618 Hom.: 42105 Cov.: 29

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.685 AC: 976375 AN: 1425690 Hom.: 340659 AF XY: 0.679 AC XY: 482989 AN XY: 711436

Gnomad4 AFR exome AF: 0.924

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.428

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.715

Gnomad4 NFE exome AF: 0.710

Gnomad4 OTH exome AF: 0.674

GnomAD4 genome AF: 0.733 AC: 111260 AN: 151738 Hom.: 42143 Cov.: 29 AF XY: 0.727 AC XY: 53906 AN XY: 74122

Gnomad4 AFR AF: 0.913

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.693

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.702

Gnomad4 OTH AF: 0.713

Alfa AF: 0.698 Hom.: 23956

Bravo AF: 0.735

Asia WGS AF: 0.423 AC: 1475 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	-0.59
Cadd	Benign	7.4
Dann	Benign	0.39

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs151472; hg19: chr18-3447871; COSMIC: COSV57906662; COSMIC: COSV57906662;