Genetic Variant TRIM28:p.Ala8Ala (chr19-58544781-C-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_005762.3(TRIM28):c.24C>G(p.Ala8Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,172,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

TRIM28
NM_005762.3 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.325

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP7

Synonymous conserved (PhyloP=-0.325 with no splicing effect.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM28	NM_005762.3 link	c.24C>G	p.Ala8Ala	synonymous_variant	Exon 1 of 17	ENST00000253024.10	NP_005753.1	Q13263-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIM28	ENST00000253024.10 link	c.24C>G	p.Ala8Ala	synonymous_variant	Exon 1 of 17	1	NM_005762.3	ENSP00000253024.4	Q13263-1
TRIM28	ENST00000341753.10 link	c.24C>G	p.Ala8Ala	synonymous_variant	Exon 1 of 15	1		ENSP00000342232.5	Q13263-2
TRIM28	ENST00000594806.5 link	c.-222-157C>G		intron_variant	Intron 1 of 6	5		ENSP00000473126.1	M0R3C0
TRIM28	ENST00000593582.5 link	c.76+570C>G		intron_variant	Intron 1 of 4	3		ENSP00000472586.1	M0R2I3

Frequencies

GnomAD3 genomes

AF:

0.0000403

AC:

AN:

148988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

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:

0.0000150

Gnomad OTH

AF:

0.000487

GnomAD4 exome

AF:

0.00000977

AC:

AN:

1023116

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

485086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20502

American (AMR)

AF:

0.00

AC:

AN:

6368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11400

East Asian (EAS)

AF:

0.00

AC:

AN:

19904

South Asian (SAS)

AF:

0.00

AC:

AN:

21674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2602

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

884008

Other (OTH)

AF:

0.0000257

AC:

AN:

38868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000403

AC:

AN:

148988

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

72654

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41064

American (AMR)

AF:

0.000200

AC:

AN:

15014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66804

Other (OTH)

AF:

0.000487

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 8 of the TRIM28 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TRIM28 protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TRIM28-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing 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

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.9

(source)

DANN

Benign

0.73

PromoterAI

0.030

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

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.

19-58544781-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over