NM_030912.3:c.1375C>T

Variant names:

• chr10-102657073-C-T
• rs866294686
• NM_030912.3:c.1375C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_030912.3(TRIM8):​c.1375C>T​(p.Gln459*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM8 NM_030912.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.50
• Publications: 4 publications found

Genes affected

TRIM8 (HGNC:15579): (tripartite motif containing 8) This gene encodes a member of the tripartite motif (TRIM) protein family. Based on similarities to other proteins, the encoded protein is suspected to be an E3 ubiquitin-protein ligase. Regulation of this gene may be altered in some cancers. Mutations resulting in a truncated protein product have been observed in early-onset epileptic encephalopathy (EOEE). [provided by RefSeq, Sep 2016]

TRIM8 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis and neurodevelopmental syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102657073-C-T is Pathogenic according to our data. Variant chr10-102657073-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 584442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM8	NM_030912.3	c.1375C>T	p.Gln459*	stop_gained	Exon 6 of 6	ENST00000643721.2	NP_112174.2
TRIM8	NM_001345950.1	c.1279C>T	p.Gln427*	stop_gained	Exon 5 of 5		NP_001332879.1
TRIM8	NR_144321.1	n.1523C>T		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM8	ENST00000643721.2	c.1375C>T	p.Gln459*	stop_gained	Exon 6 of 6		NM_030912.3	ENSP00000496301.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis and neurodevelopmental syndrome Pathogenic:3

Aug 09, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS2, PS4, PM2 -

Aug 04, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

May 20, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1375C>T (p.Q459*) alteration, located in coding exon 6 of the TRIM8 gene, consists of a C to T substitution at nucleotide position 1375. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 459. This alteration occurs at the 3' terminus of the TRIM8 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 16.9% of the protein. The exact functional effect of this alteration is unknown and loss of function of TRIM8 has not been established as a mechanism of disease. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported to occur de novo in multiple individuals affected with a neurodevelopmental disorder and seizures (Assoum, 2018; Weng, 2021; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Dec 02, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 93 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30244534, 33508234) -

TRIM8-related epileptic encephalopathy Pathogenic:1

May 14, 2018

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis;C0036572:Seizure;C4022738:Neurodevelopmental delay Pathogenic:1

Jan 27, 2021

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.29	T
MetaRNN	Pathogenic	0.80	D
PhyloP100		7.5
GERP RS		5.4
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs866294686; hg19: chr10-104416830;