chr18-3448075-G-C

Position:

• chr18-3448075-G-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.126-889C>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 0.00387 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: LOC124904237 XR_007066269.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.412

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=-0.63).
• 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/exons	MANE	UniProt
LOC124904237	XR_007066269.1	n.126-889C>G		intron_variant, non_coding_transcript_variant
TGIF1	NM_001278686.3	c.-44-8279G>C		intron_variant
TGIF1	NM_173207.4	c.58+278G>C		intron_variant
TGIF1	NM_174886.3	c.-44-8279G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000401449.5	c.-44-8279G>C		intron_variant		2
TGIF1	ENST00000548489.6	c.-44-8279G>C		intron_variant		3
TGIF1	ENST00000550958.5	c.-44-8279G>C		intron_variant		3

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

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;