Genetic Variant TRIM48:p.Ser49Arg (chr11-55265002-C-G) – 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.147C>G(p.Ser49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,584,646 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 30)

Exomes 𝑓: 0.00012 ( 21 hom. )

Consequence

TRIM48
NM_024114.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.228

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=0.03686309).

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM48	NM_024114.5 link	c.147C>G	p.Ser49Arg	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.147C>G	p.Ser49Arg	missense_variant	Exon 2 of 6	1	NM_024114.5	ENSP00000402414.2		Q8IWZ4

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

147942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000683

Gnomad ASJ

AF:

0.00263

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0000448

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000180

AC:

AN:

244990

Hom.:

AF XY:

0.000212

AC XY:

AN XY:

132258

show subpopulations

Gnomad AFR exome

AF:

0.000568

Gnomad AMR exome

AF:

0.0000884

Gnomad ASJ exome

AF:

0.00181

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000981

Gnomad OTH exome

AF:

0.000501

GnomAD4 exome

AF:

0.000123

AC:

177

AN:

1436590

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

713690

show subpopulations

Gnomad4 AFR exome

AF:

0.000301

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.00306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000500

Gnomad4 OTH exome

AF:

0.000422

GnomAD4 genome

AF:

0.000230

AC:

AN:

148056

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

AN XY:

72122

show subpopulations

Gnomad4 AFR

AF:

0.000493

Gnomad4 AMR

AF:

0.0000683

Gnomad4 ASJ

AF:

0.00263

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000448

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.000457

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.000151

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.000120

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.147C>G (p.S49R) alteration is located in exon 2 (coding exon 2) of the TRIM48 gene. This alteration results from a C to G substitution at nucleotide position 147, causing the serine (S) at amino acid position 49 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

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.95

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.19

M_CAP

Benign

0.0012

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.15

Sift

Uncertain

0.018

Sift4G

Uncertain

0.029

Vest4

0.27

MVP

0.25

MPC

0.0073

ClinPred

0.087

GERP RS

-1.2

gMVP

0.065

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