NM_173084.3:c.926C>G

Variant names:

• chr3-160438258-G-C
• rs201846537
• NM_173084.3:c.926C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173084.3(TRIM59):​c.926C>G​(p.Pro309Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P309L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIM59 NM_173084.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 0 publications found

Genes affected

TRIM59 (HGNC:30834): (tripartite motif containing 59) Predicted to enable ubiquitin protein ligase activity. Acts upstream of or within negative regulation of I-kappaB kinase/NF-kappaB signaling. Predicted to be located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TRIM59-IFT80 (HGNC:56756): (TRIM59-IFT80 readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring TRIM59 (tripartite motif containing 59) and IFT80 (intraflagellar transport 80) genes on chromosome 3. The readthrough transcript is unlikely to produce a protein product. [provided by RefSeq, Jun 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118890435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173084.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM59	NM_173084.3	MANE Select	c.926C>G	p.Pro309Arg	missense	Exon 3 of 3	NP_775107.1	Q8IWR1-1
	TRIM59-IFT80	NR_148401.1		n.1121C>G		non_coding_transcript_exon	Exon 3 of 19
	TRIM59-IFT80	NR_148402.1		n.1051C>G		non_coding_transcript_exon	Exon 2 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM59	ENST00000309784.9	TSL:1 MANE Select	c.926C>G	p.Pro309Arg	missense	Exon 3 of 3	ENSP00000311219.4	Q8IWR1-1
	TRIM59-IFT80	ENST00000483754.1	TSL:2	n.926C>G		non_coding_transcript_exon	Exon 3 of 19	ENSP00000456272.1	H3BRJ5
	TRIM59	ENST00000870881.1		c.926C>G	p.Pro309Arg	missense	Exon 4 of 4	ENSP00000540940.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461398 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726946

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0063	T
Eigen	Benign	0.017
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.047
Sift	Benign	0.16	T
Sift4G	Benign	0.36	T
Polyphen		0.26	B
Vest4		0.18
MutPred		0.49		Gain of glycosylation at S313 (P = 0.0041)
MVP		0.29
MPC		0.090
ClinPred		0.21	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.15
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs201846537; hg19: chr3-160156046;