10-102644618-A-G

Position:

• chr10-102644618-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_030912.3(TRIM8):​c.1A>G​(p.Met1?) variant causes a start lost change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIM8 NM_030912.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM8	NM_030912.3	c.1A>G	p.Met1?	start_lost	1/6	ENST00000643721.2
TRIM8	NM_001345950.1	c.1A>G	p.Met1?	start_lost	1/5
TRIM8	NR_144321.1	n.124A>G		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM8	ENST00000643721.2	c.1A>G	p.Met1?	start_lost	1/6		NM_030912.3	P1
TRIM8	ENST00000302424.12	c.1A>G	p.Met1?	start_lost	1/5	1
TRIM8	ENST00000710327.1	c.1A>G	p.Met1?	start_lost	1/6			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2021

Not observed in large population cohorts (Lek et al., 2016); Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.71	.;N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.25	B;.
Vest4		0.89
MutPred		0.98		Loss of ubiquitination at K6 (P = 0.1166);Loss of ubiquitination at K6 (P = 0.1166);
MVP		0.92
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104404375;