11-89798546-G-A

Variant names:

• chr11-89798546-G-A
• rs759505716
• NM_020358.2:c.943C>T

Variant summary

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

The NM_020358.2(TRIM49):​c.943C>T​(p.His315Tyr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRIM49 NM_020358.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.558

Genes affected

TRIM49 (HGNC:13431): (tripartite motif containing 49) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This gene has been found to be preferentially expressed in testis. Related pseudogenes and gene duplicates have also been identified on chromosome 11. [provided by RefSeq, Aug 2010]

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=0.12833464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM49	NM_020358.2	c.943C>T	p.His315Tyr	missense_variant	Exon 8 of 8	ENST00000329758.5	NP_065091.1
TRIM49	XM_017018027.3	c.712C>T	p.His238Tyr	missense_variant	Exon 5 of 5		XP_016873516.1
TRIM49	XM_024448617.2	c.738+3156C>T		intron_variant	Intron 3 of 5		XP_024304385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM49	ENST00000329758.5	c.943C>T	p.His315Tyr	missense_variant	Exon 8 of 8	1	NM_020358.2	ENSP00000327604.1
TRIM49	ENST00000532501.2	c.712C>T	p.His238Tyr	missense_variant	Exon 6 of 6	5		ENSP00000431618.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 240816 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130932

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: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.95e-7 AC: 1 AN: 1439006 Hom.: 0 Cov.: 63 AF XY: 0.00 AC XY: 0 AN XY: 716104

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.943C>T (p.H315Y) alteration is located in exon 8 (coding exon 6) of the TRIM49 gene. This alteration results from a C to T substitution at nucleotide position 943, causing the histidine (H) at amino acid position 315 to be replaced by a tyrosine (Y). 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	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.16
DANN	Benign	0.23
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.098
Sift	Benign	0.29	T;T
Sift4G	Benign	0.10	T;D
Polyphen		0.84	P;.
Vest4		0.16
MutPred		0.66		Loss of catalytic residue at H315 (P = 0.0236);.;
MVP		0.043
MPC		1.4
ClinPred		0.12	T
GERP RS		0.82
Varity_R		0.049
gMVP		0.026

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: rs759505716; hg19: chr11-89531714;