chr19-58544840-G-T

Position:

chr19-58544840-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005762.3(TRIM28):c.83G>T(p.Gly28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,281,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

TRIM28
NM_005762.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.305

Variant links:

Genes affected

TRIM28 (HGNC:16384): (tripartite motif containing 28) The protein encoded by this gene mediates transcriptional control by interaction with the Kruppel-associated box repression domain found in many transcription factors. The protein localizes to the nucleus and is thought to associate with specific chromatin regions. The protein is a member of the tripartite motif family. This tripartite motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. [provided by RefSeq, Jul 2008]

TRIM28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19447848).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM28	NM_005762.3 linkuse as main transcript	c.83G>T	p.Gly28Val	missense_variant	1/17	ENST00000253024.10	NP_005753.1	Q13263-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRIM28	ENST00000253024.10 linkuse as main transcript	c.83G>T	p.Gly28Val	missense_variant	1/17	1	NM_005762.3	ENSP00000253024.4	Q13263-1
TRIM28	ENST00000341753.10 linkuse as main transcript	c.83G>T	p.Gly28Val	missense_variant	1/15	1		ENSP00000342232.5	Q13263-2
TRIM28	ENST00000594806.5 linkuse as main transcript	c.-222-98G>T		intron_variant		5		ENSP00000473126.1	M0R3C0
TRIM28	ENST00000593582.5 linkuse as main transcript	c.77-585G>T		intron_variant		3		ENSP00000472586.1	M0R2I3

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000887

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000690

AC:

AN:

1130654

Hom.:

Cov.:

AF XY:

0.0000659

AC XY:

AN XY:

545926

show subpopulations

Gnomad4 AFR exome

AF:

0.0000438

Gnomad4 AMR exome

AF:

0.0000952

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:

0.0000739

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151068

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73762

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000887

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 28 of the TRIM28 protein (p.Gly28Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRIM28-related conditions. ClinVar contains an entry for this variant (Variation ID: 2444882). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Wilms tumor 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Mar 02, 2023

The TRIM28 c.83G>T (p.Gly28Val) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/), however data at this position may not be reliable due to mean depth of coverage <30X. The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with a personal or family history of Wilms tumor. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.53

T;T

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

N;N

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.53

N;N

REVEL

Benign

0.041

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.055

T;D

Polyphen

0.12

B;B

Vest4

0.14

MutPred

0.23

Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);

MVP

0.46

MPC

0.79

ClinPred

0.13

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.048

gMVP

0.30

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