14-51000689-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001387360.1(TRIM9):c.1458A>C(p.Gln486His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRIM9 NM_001387360.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.532

Genes affected

TRIM9 (HGNC:16288): (tripartite motif containing 9) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. Its function has not been identified. Alternate splicing of this gene generates two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38561505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM9	NM_001387360.1	c.1458A>C	p.Gln486His	missense_variant	6/13	ENST00000684578.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM9	ENST00000684578.1	c.1458A>C	p.Gln486His	missense_variant	6/13		NM_001387360.1
TRIM9	ENST00000298355.7	c.1458A>C	p.Gln486His	missense_variant	6/10	1		P1
TRIM9	ENST00000360392.4	c.1458A>C	p.Gln486His	missense_variant	6/7	1
TRIM9	ENST00000338969.9	c.1446A>C	p.Gln482His	missense_variant	6/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Nov 15, 2021

The c.1458A>C (p.Q486H) alteration is located in exon 6 (coding exon 6) of the TRIM9 gene. This alteration results from a A to C substitution at nucleotide position 1458, causing the glutamine (Q) at amino acid position 486 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.030	D;D;D
Sift4G	Benign	0.067	T;T;T
Polyphen		0.92	P;D;P
Vest4		0.51
MutPred		0.57		Loss of solvent accessibility (P = 0.0635);.;Loss of solvent accessibility (P = 0.0635);
MVP		0.20
MPC		1.7
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.21
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2054864403; hg19: chr14-51467407;