19-58544887-G-C

Position:

chr19-58544887-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005762.3(TRIM28):c.130G>C(p.Ala44Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,370,048 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 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

TRIM28
NM_005762.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.69

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.346803).

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM28	NM_005762.3 linkuse as main transcript	c.130G>C	p.Ala44Pro	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.130G>C	p.Ala44Pro	missense_variant	1/17	1	NM_005762.3	ENSP00000253024.4	Q13263-1
TRIM28	ENST00000341753.10 linkuse as main transcript	c.130G>C	p.Ala44Pro	missense_variant	1/15	1		ENSP00000342232.5	Q13263-2
TRIM28	ENST00000594806.5 linkuse as main transcript	c.-222-51G>C		intron_variant		5		ENSP00000473126.1	M0R3C0
TRIM28	ENST00000593582.5 linkuse as main transcript	c.77-538G>C		intron_variant		3		ENSP00000472586.1	M0R2I3

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000442

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000311

AC:

AN:

16074

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

10392

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:

0.000593

Gnomad OTH exome

AF:

0.00205

GnomAD4 exome

AF:

0.000442

AC:

539

AN:

1218160

Hom.:

Cov.:

AF XY:

0.000439

AC XY:

262

AN XY:

596312

show subpopulations

Gnomad4 AFR exome

AF:

0.0000844

Gnomad4 AMR exome

AF:

0.0000918

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:

0.000515

Gnomad4 OTH exome

AF:

0.000403

GnomAD4 genome

AF:

0.000244

AC:

AN:

151888

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000442

Gnomad4 OTH

AF:

0.000475

Bravo

AF:

0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.130G>C (p.A44P) alteration is located in exon 1 (coding exon 1) of the TRIM28 gene. This alteration results from a G to C substitution at nucleotide position 130, causing the alanine (A) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 44 of the TRIM28 protein (p.Ala44Pro). This variant is present in population databases (no rsID available, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. 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: 2347242). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.031

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.53

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.55

N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.69

N;N

REVEL

Benign

0.18

Sift

Benign

0.044

D;T

Sift4G

Benign

0.24

T;D

Polyphen

0.99

D;D

Vest4

0.16

MutPred

0.30

Gain of glycosylation at A44 (P = 0.0042);Gain of glycosylation at A44 (P = 0.0042);

MVP

0.56

MPC

0.82

ClinPred

0.071

GERP RS

2.3

Varity_R

0.083

gMVP

0.46

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