rs238132

Variant names:

• chr18-3450457-C-A
• rs238132
• NM_003244.4:c.-33C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-3450457-C-A
• chr18-3450457-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003244.4(TGIF1):​c.-33C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,554,452 control chromosomes in the GnomAD database, including 26,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (8088 hom., cov: 32)
  • Exomes 𝑓: 0.14 (18256 hom.)
• Consequence: TGIF1 NM_003244.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.311
• Publications: 12 publications found

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]

TGIF1 Gene-Disease associations (from GenCC):

• holoprosencephaly 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ENSG00000302876 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-3450457-C-A is Benign according to our data. Variant chr18-3450457-C-A is described in ClinVar as Benign. ClinVar VariationId is 259013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.-33C>A		5_prime_UTR_variant	Exon 1 of 3	ENST00000343820.10	NP_003235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGIF1	ENST00000343820.10	c.-33C>A		5_prime_UTR_variant	Exon 1 of 3	1	NM_003244.4	ENSP00000339631.6

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39592 AN: 151956 Hom.: 8063 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.160 AC: 25422 AN: 158684 AF XY: 0.156

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.0964

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.138

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.143 AC: 200669 AN: 1402378 Hom.: 18256 Cov.: 33 AF XY: 0.143 AC XY: 98621 AN XY: 692056

African (AFR) AF: 0.592 AC: 18756 AN: 31662

American (AMR) AF: 0.108 AC: 3891 AN: 36094

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3814 AN: 25198

East Asian (EAS) AF: 0.144 AC: 5188 AN: 35910

South Asian (SAS) AF: 0.168 AC: 13361 AN: 79394

European-Finnish (FIN) AF: 0.162 AC: 7961 AN: 49274

Middle Eastern (MID) AF: 0.197 AC: 1122 AN: 5698

European-Non Finnish (NFE) AF: 0.127 AC: 136891 AN: 1080988

Other (OTH) AF: 0.167 AC: 9685 AN: 58160

GnomAD4 genome AF: 0.261 AC: 39670 AN: 152074 Hom.: 8088 Cov.: 32 AF XY: 0.259 AC XY: 19285 AN XY: 74334

African (AFR) AF: 0.576 AC: 23878 AN: 41442

American (AMR) AF: 0.149 AC: 2275 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 491 AN: 3472

East Asian (EAS) AF: 0.153 AC: 789 AN: 5142

South Asian (SAS) AF: 0.172 AC: 828 AN: 4826

European-Finnish (FIN) AF: 0.158 AC: 1673 AN: 10588

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9061 AN: 67990

Other (OTH) AF: 0.234 AC: 495 AN: 2116

Alfa AF: 0.122 Hom.: 372

Bravo AF: 0.270

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holoprosencephaly sequence Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	-0.81
CADD	Benign	6.1
DANN	Benign	0.56
PhyloP100		-0.31
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs238132; hg19: chr18-3450455; COSMIC: COSV57910050; COSMIC: COSV57910050;