Genetic Variant NM_145720.4:c.1445T>G (chr4-152769560-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_145720.4(TIGD4):c.1445T>G(p.Leu482Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TIGD4
NM_145720.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74

Variant links:

Genes affected

TIGD4 (HGNC:18335): (tigger transposable element derived 4) The protein encoded by this gene belongs to the tigger subfamily of the pogo superfamily of DNA-mediated transposons in humans. These proteins are related to DNA transposons found in fungi and nematodes, and more distantly to the Tc1 and mariner transposases. They are also very similar to the major mammalian centromere protein B. The exact function of this gene is not known. [provided by RefSeq, Jul 2008]

TIGD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIGD4	NM_145720.4 link	c.1445T>G	p.Leu482Arg	missense_variant	Exon 2 of 2	ENST00000304337.3	NP_663772.1	Q8IY51
TIGD4	XM_005262807.5 link	c.1445T>G	p.Leu482Arg	missense_variant	Exon 3 of 3		XP_005262864.1	Q8IY51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIGD4	ENST00000304337.3 link	c.1445T>G	p.Leu482Arg	missense_variant	Exon 2 of 2	1	NM_145720.4	ENSP00000355162.2		Q8IY51

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244242

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453976

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722660

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1445T>G (p.L482R) alteration is located in exon 2 (coding exon 1) of the TIGD4 gene. This alteration results from a T to G substitution at nucleotide position 1445, causing the leucine (L) at amino acid position 482 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

M_CAP

Benign

0.011

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.92

MutPred

0.62

Loss of stability (P = 0.0027);

MVP

0.12

MPC

0.18

ClinPred

0.96

GERP RS

6.1

Varity_R

0.67

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over