18-3447827-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The XR_007066269.1(LOC124904237):n.126-641G>C 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 0.000697 in 1,613,866 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (7 hom.)
• Consequence: LOC124904237 XR_007066269.1 intron, non_coding_transcript
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0100

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 18-3447827-C-G is Benign according to our data. Variant chr18-3447827-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1204789.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124904237	XR_007066269.1	n.126-641G>C		intron_variant, non_coding_transcript_variant
TGIF1	NM_001278686.3	c.-44-8527C>G		intron_variant
TGIF1	NM_173207.4	c.58+30C>G		intron_variant
TGIF1	NM_174886.3	c.-44-8527C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGIF1	ENST00000401449.5	c.-44-8527C>G		intron_variant		2
TGIF1	ENST00000548489.6	c.-44-8527C>G		intron_variant		3
TGIF1	ENST00000550958.5	c.-44-8527C>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000994 AC: 250 AN: 251450 Hom.: 1 AF XY: 0.000684 AC XY: 93 AN XY: 135910

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000374 AC: 547 AN: 1461612 Hom.: 7 Cov.: 30 AF XY: 0.000347 AC XY: 252 AN XY: 727146

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74446

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.00434

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	3.2
Dann	Benign	0.28

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113866405; hg19: chr18-3447825;