Genetic Variant TRIM49B:p.Pro25Leu (chr11-49031673-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001206626.2(TRIM49B):c.74C>T(p.Pro25Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TRIM49B
NM_001206626.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Variant links:

Genes affected

TRIM49B (HGNC:42955): (tripartite motif containing 49B)

TRIM49B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM49B	NM_001206626.2 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 2 of 7	ENST00000332682.9	NP_001193555.1	A6NDI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM49B	ENST00000332682.9 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 2 of 7	1	NM_001206626.2	ENSP00000330216.7		A6NDI0
TRIM49B	ENST00000622138.4 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 3 of 8	1		ENSP00000481457.1		A6NDI0

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250796

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135634

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727144

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74C>T (p.P25L) alteration is located in exon 1 (coding exon 1) of the TRIM49B gene. This alteration results from a C to T substitution at nucleotide position 74, causing the proline (P) at amino acid position 25 to be replaced by a leucine (L). 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

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.0084

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.5

H;H

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-8.5

.;D

REVEL

Benign

0.19

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.74

MutPred

0.64

Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.50

MPC

0.046

ClinPred

1.0

GERP RS

0.49

Varity_R

0.37

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