18-3447727-C-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.126-541G>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 0.041 in 1,613,918 control chromosomes in the GnomAD database, including 1,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (527 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1429 hom.)
• Consequence: LOC124904237 XR_007066269.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.453

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=-0.71).
• BP6: Variant 18-3447727-C-T is Benign according to our data. Variant chr18-3447727-C-T is described in ClinVar as [Benign]. Clinvar id is 675019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124904237	XR_007066269.1	n.126-541G>A		intron_variant, non_coding_transcript_variant
TGIF1	NM_173207.4	c.-13C>T		5_prime_UTR_variant	1/3
TGIF1	NM_001278686.3	c.-44-8627C>T		intron_variant
TGIF1	NM_174886.3	c.-44-8627C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000618001.4	c.-13C>T		5_prime_UTR_variant	1/3	2
TGIF1	ENST00000401449.5	c.-44-8627C>T		intron_variant		2
TGIF1	ENST00000548489.6	c.-44-8627C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0694 AC: 10550 AN: 152100 Hom.: 524 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0867

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0688

GnomAD3 exomes AF: 0.0482 AC: 12110 AN: 251492 Hom.: 452 AF XY: 0.0461 AC XY: 6265 AN XY: 135920

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.0963

Gnomad SAS exome AF: 0.0180

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0380 AC: 55599 AN: 1461700 Hom.: 1429 Cov.: 31 AF XY: 0.0375 AC XY: 27250 AN XY: 727162

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.0597

Gnomad4 EAS exome AF: 0.0779

Gnomad4 SAS exome AF: 0.0198

Gnomad4 FIN exome AF: 0.0835

Gnomad4 NFE exome AF: 0.0320

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0694 AC: 10563 AN: 152218 Hom.: 527 Cov.: 32 AF XY: 0.0702 AC XY: 5226 AN XY: 74414

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.0869

Gnomad4 SAS AF: 0.0296

Gnomad4 FIN AF: 0.0817

Gnomad4 NFE AF: 0.0333

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0563 Hom.: 124

Bravo AF: 0.0709

Asia WGS AF: 0.0500 AC: 173 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 19, 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	-0.71
Cadd	Benign	1.0
Dann	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs238137; hg19: chr18-3447725;