18-3457572-A-G

Position:

• chr18-3457572-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003244.4(TGIF1):​c.451A>G​(p.Thr151Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,910 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (3 hom.)
• Consequence: TGIF1 NM_003244.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 1.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020125508).
• BP6: Variant 18-3457572-A-G is Benign according to our data. Variant chr18-3457572-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 6981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3457572-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000986 (15/152056) while in subpopulation SAS AF= 0.00229 (11/4812). AF 95% confidence interval is 0.00128. There are 1 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGIF1	NM_003244.4	c.451A>G	p.Thr151Ala	missense_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.451A>G	p.Thr151Ala	missense_variant	3/3	1	NM_003244.4	ENSP00000339631	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151938 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251420 Hom.: 1 AF XY: 0.000191 AC XY: 26 AN XY: 135886

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1461854 Hom.: 3 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152056 Hom.: 1 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000442 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 4 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.17	.;.;.;.;.;T;.;.;.;.;.;T;.;T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.57	T;.;T;.;T;T;T;.;T;.;.;T;T;T;.;T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	.;.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	0.64	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.080	N;N;N;.;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.35	T;T;D;.;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;.;.;.;.;.;B;B;.;.;B;.;.;.;.;.
Vest4		0.21, 0.21, 0.11, 0.18, 0.66, 0.13, 0.19, 0.20, 0.21, 0.12
MVP		0.69
MPC		0.36
ClinPred		0.011	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.49

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: rs121909068; hg19: chr18-3457570;