Genetic Variant TRIM48:p.Pro63Ser (chr11-55265042-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024114.5(TRIM48):c.187C>T(p.Pro63Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000726 in 1,584,046 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P63T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000077 ( 9 hom. )

Consequence

TRIM48
NM_024114.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.569

Variant links:

Genes affected

TRIM48 (HGNC:19021): (tripartite motif containing 48) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in innate immune response; protein ubiquitination; and regulation of gene expression. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRIM48 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03376451).

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM48	NM_024114.5 link	c.187C>T	p.Pro63Ser	missense_variant	Exon 2 of 6	ENST00000417545.5	NP_077019.2	Q8IWZ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM48	ENST00000417545.5 link	c.187C>T	p.Pro63Ser	missense_variant	Exon 2 of 6	1	NM_024114.5	ENSP00000402414.2		Q8IWZ4

Frequencies

GnomAD3 genomes

AF:

0.0000338

AC:

AN:

147886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

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:

0.0000598

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000285

AC:

AN:

245378

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

132368

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:

0.0000624

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000766

AC:

110

AN:

1436046

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

713382

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000100

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000338

AC:

AN:

148000

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

72144

show subpopulations

Gnomad4 AFR

AF:

0.0000247

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:

0.0000598

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000839

AC:

EpiCase

AF:

0.0000551

EpiControl

AF:

0.000180

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187C>T (p.P63S) alteration is located in exon 2 (coding exon 2) of the TRIM48 gene. This alteration results from a C to T substitution at nucleotide position 187, causing the proline (P) at amino acid position 63 to be replaced by a serine (S). 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

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.5

DANN

Benign

0.34

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0017

M_CAP

Benign

0.0057

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.88

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.2

REVEL

Benign

0.20

Sift

Benign

0.38

Sift4G

Benign

0.25

Vest4

0.13

MVP

0.15

MPC

0.0031

ClinPred

0.027

GERP RS

-1.2

gMVP

0.020

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