18-3448073-CGG-CGGGG

Variant names:

• chr18-3448073-C-CGG
• rs34135793
• NM_173207.4:c.58+283_58+284dupGG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_173207.4(TGIF1):​c.58+283_58+284dupGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 947,900 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TGIF1 NM_173207.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_173207.4	c.58+283_58+284dupGG		intron_variant	Intron 1 of 2		NP_775299.1
TGIF1	NM_001278686.3	c.-44-8274_-44-8273dupGG		intron_variant	Intron 2 of 3		NP_001265615.1
TGIF1	NM_174886.3	c.-44-8274_-44-8273dupGG		intron_variant	Intron 2 of 3		NP_777480.1
LOC124904237	XR_007066269.1	n.126-889_126-888dupCC		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000618001.4	c.58+276_58+277insGG		intron_variant	Intron 1 of 2	2		ENSP00000483499.1
TGIF1	ENST00000401449.5	c.-44-8281_-44-8280insGG		intron_variant	Intron 2 of 3	2		ENSP00000385206.1
TGIF1	ENST00000548489.6	c.-44-8281_-44-8280insGG		intron_variant	Intron 2 of 3	3		ENSP00000447747.2

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 34 AN: 141496 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.000519

GnomAD4 exome AF: 0.0000136 AC: 11 AN: 806278 Hom.: 0 Cov.: 29 AF XY: 0.0000134 AC XY: 5 AN XY: 372786

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000200

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000136

Gnomad4 OTH exome AF: 0.0000379

GnomAD4 genome AF: 0.000233 AC: 33 AN: 141622 Hom.: 0 Cov.: 29 AF XY: 0.000189 AC XY: 13 AN XY: 68630

Gnomad4 AFR AF: 0.000713

Gnomad4 AMR AF: 0.000285

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000153

Gnomad4 OTH AF: 0.000513

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34135793; hg19: chr18-3448071;