rs2229337

Positions:

• chr18-3457541-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003244.4(TGIF1):​c.420A>G​(p.Pro140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 1,613,952 control chromosomes in the GnomAD database, including 9,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2259 hom., cov: 32)
  • Exomes 𝑓: 0.083 (7007 hom.)
• Consequence: TGIF1 NM_003244.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.40

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 18-3457541-A-G is Benign according to our data. Variant chr18-3457541-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.420A>G	p.Pro140=	synonymous_variant	3/3	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10	c.420A>G	p.Pro140=	synonymous_variant	3/3	1	NM_003244.4	ENSP00000339631	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21087 AN: 151952 Hom.: 2258 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.102 AC: 25699 AN: 251440 Hom.: 2075 AF XY: 0.0998 AC XY: 13567 AN XY: 135906

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.0483

Gnomad ASJ exome AF: 0.0879

Gnomad EAS exome AF: 0.287

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.0496

Gnomad NFE exome AF: 0.0690

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0826 AC: 120775 AN: 1461882 Hom.: 7007 Cov.: 31 AF XY: 0.0831 AC XY: 60402 AN XY: 727244

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.0530

Gnomad4 ASJ exome AF: 0.0913

Gnomad4 EAS exome AF: 0.267

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0489

Gnomad4 NFE exome AF: 0.0678

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.139 AC: 21110 AN: 152070 Hom.: 2259 Cov.: 32 AF XY: 0.138 AC XY: 10235 AN XY: 74326

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.0835

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.0691

Gnomad4 OTH AF: 0.129

Alfa AF: 0.106 Hom.: 669

Bravo AF: 0.147

Asia WGS AF: 0.190 AC: 662 AN: 3478

EpiCase AF: 0.0760

EpiControl AF: 0.0784

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holoprosencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Holoprosencephaly sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.035
DANN	Benign	0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229337; hg19: chr18-3457539;