Genetic Variant TRIM49B:p.Phe103Val (chr11-49031906-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001206626.2(TRIM49B):c.307T>G(p.Phe103Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRIM49B
NM_001206626.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

Variant links:

Genes affected

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

TRIM49B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM49B	NM_001206626.2 link	c.307T>G	p.Phe103Val	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.307T>G	p.Phe103Val	missense_variant	Exon 2 of 7	1	NM_001206626.2	ENSP00000330216.7		A6NDI0
TRIM49B	ENST00000622138.4 link	c.307T>G	p.Phe103Val	missense_variant	Exon 3 of 8	1		ENSP00000481457.1		A6NDI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250876

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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.307T>G (p.F103V) alteration is located in exon 1 (coding exon 1) of the TRIM49B gene. This alteration results from a T to G substitution at nucleotide position 307, causing the phenylalanine (F) at amino acid position 103 to be replaced by a valine (V). 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

0.45

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.060

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.89

.;D

M_CAP

Benign

0.0051

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

4.5

H;H

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.5

.;D

REVEL

Benign

0.16

Sift

Uncertain

0.0010

.;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.56

MutPred

0.76

Gain of ubiquitination at K100 (P = 0.0762);Gain of ubiquitination at K100 (P = 0.0762);

MVP

0.54

MPC

0.043

ClinPred

0.96

GERP RS

0.49

Varity_R

0.48

gMVP

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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