3-160438054-T-C

Variant names:

• chr3-160438054-T-C
• rs774589319
• NM_173084.3:c.1130A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173084.3(TRIM59):​c.1130A>G​(p.Asn377Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,452,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TRIM59 NM_173084.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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]

ENSG00000248710 (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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040967762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM59	NM_173084.3	c.1130A>G	p.Asn377Ser	missense_variant	Exon 3 of 3	ENST00000309784.9	NP_775107.1
TRIM59-IFT80	NR_148401.1	n.1147+178A>G		intron_variant	Intron 3 of 18
TRIM59-IFT80	NR_148402.1	n.1077+178A>G		intron_variant	Intron 2 of 20
TRIM59-IFT80	NR_148403.1	n.1344+178A>G		intron_variant	Intron 2 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM59	ENST00000309784.9	c.1130A>G	p.Asn377Ser	missense_variant	Exon 3 of 3	1	NM_173084.3	ENSP00000311219.4
ENSG00000248710	ENST00000483754.1	n.952+178A>G		intron_variant	Intron 3 of 18	2		ENSP00000456272.1
TRIM59	ENST00000543469.1	c.952+178A>G		intron_variant	Intron 2 of 2	5		ENSP00000444313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1452736 Hom.: 0 Cov.: 33 AF XY: 0.00000831 AC XY: 6 AN XY: 722238

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: 0.00000901

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1130A>G (p.N377S) alteration is located in exon 3 (coding exon 1) of the TRIM59 gene. This alteration results from a A to G substitution at nucleotide position 1130, causing the asparagine (N) at amino acid position 377 to be replaced by a serine (S). 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	0.065
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.88
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.013
Sift	Benign	0.57	T
Sift4G	Benign	0.68	T
Polyphen		0.0030	B
Vest4		0.070
MutPred		0.21		Gain of disorder (P = 0.0444);
MVP		0.20
MPC		0.051
ClinPred		0.039	T
GERP RS		3.4
Varity_R		0.020
gMVP		0.077

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: rs774589319; hg19: chr3-160155842;