18-3448075-G-C

Variant names:

• chr18-3448075-G-C
• rs182953695
• NM_173207.4:c.58+278G>C

Variant summary

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

The NM_173207.4(TGIF1):​c.58+278G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 978,882 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (62 hom., cov: 30)
  • Exomes 𝑓: 0.0015 (30 hom.)
• Consequence: TGIF1 NM_173207.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.412

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 18-3448075-G-C is Benign according to our data. Variant chr18-3448075-G-C is described in ClinVar as [Benign]. Clinvar id is 1263319.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_173207.4	c.58+278G>C		intron_variant	Intron 1 of 2		NP_775299.1
TGIF1	NM_001278686.3	c.-44-8279G>C		intron_variant	Intron 2 of 3		NP_001265615.1
TGIF1	NM_174886.3	c.-44-8279G>C		intron_variant	Intron 2 of 3		NP_777480.1
LOC124904237	XR_007066269.1	n.126-889C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000618001.4	c.58+278G>C		intron_variant	Intron 1 of 2	2		ENSP00000483499.1
TGIF1	ENST00000401449.5	c.-44-8279G>C		intron_variant	Intron 2 of 3	2		ENSP00000385206.1
TGIF1	ENST00000548489.6	c.-44-8279G>C		intron_variant	Intron 2 of 3	3		ENSP00000447747.2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2524 AN: 146102 Hom.: 62 Cov.: 30

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00463

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000602

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000360

Gnomad OTH AF: 0.0151

GnomAD4 exome AF: 0.00151 AC: 1255 AN: 832662 Hom.: 30 Cov.: 29 AF XY: 0.00141 AC XY: 544 AN XY: 384532

Gnomad4 AFR exome AF: 0.0663

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000551

Gnomad4 SAS exome AF: 0.000729

Gnomad4 FIN exome AF: 0.00362

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.0173 AC: 2534 AN: 146220 Hom.: 62 Cov.: 30 AF XY: 0.0174 AC XY: 1238 AN XY: 71232

Gnomad4 AFR AF: 0.0622

Gnomad4 AMR AF: 0.00463

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000602

Gnomad4 NFE AF: 0.000360

Gnomad4 OTH AF: 0.0149

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.9
DANN	Benign	0.58

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs182953695; hg19: chr18-3448073;