11-49034196-G-A

Position:

• chr11-49034196-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001206626.2(TRIM49B):​c.558G>A​(p.Met186Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIM49B NM_001206626.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.312

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18655226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM49B	NM_001206626.2	c.558G>A	p.Met186Ile	missense_variant	4/7	ENST00000332682.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM49B	ENST00000332682.9	c.558G>A	p.Met186Ile	missense_variant	4/7	1	NM_001206626.2	P1
TRIM49B	ENST00000622138.4	c.558G>A	p.Met186Ile	missense_variant	5/8	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.558G>A (p.M186I) alteration is located in exon 3 (coding exon 3) of the TRIM49B gene. This alteration results from a G to A substitution at nucleotide position 558, causing the methionine (M) at amino acid position 186 to be replaced by an isoleucine (I). 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	0.36
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.1
DANN	Benign	0.64
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.0043	N
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.24	T;T
Vest4		0.29
MutPred		0.66		Loss of catalytic residue at M186 (P = 0.0589);Loss of catalytic residue at M186 (P = 0.0589);
MVP		0.18
MPC		2.2
ClinPred		0.049	T
GERP RS		0.69
Varity_R		0.16
gMVP		0.056

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

Other links and lift over

dbSNP: rs746729223; hg19: chr11-49055748;