rs386834143
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPM2PP3_StrongPP5_Moderate
The NM_018965.4(TREM2):c.40G>T(p.Glu14Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TREM2
NM_018965.4 stop_gained, splice_region
NM_018965.4 stop_gained, splice_region
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.02
Genes affected
TREM2 (HGNC:17761): (triggering receptor expressed on myeloid cells 2) This gene encodes a membrane protein that forms a receptor signaling complex with the TYRO protein tyrosine kinase binding protein. The encoded protein functions in immune response and may be involved in chronic inflammation by triggering the production of constitutive inflammatory cytokines. Defects in this gene are a cause of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 6-41163043-C-A is Pathogenic according to our data. Variant chr6-41163043-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 56724.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-41163043-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TREM2 | NM_018965.4 | c.40G>T | p.Glu14Ter | stop_gained, splice_region_variant | 1/5 | ENST00000373113.8 | NP_061838.1 | |
TREM2 | NM_001271821.2 | c.40G>T | p.Glu14Ter | stop_gained, splice_region_variant | 1/4 | NP_001258750.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TREM2 | ENST00000373113.8 | c.40G>T | p.Glu14Ter | stop_gained, splice_region_variant | 1/5 | 1 | NM_018965.4 | ENSP00000362205 | P1 | |
TREM2 | ENST00000373122.8 | c.40G>T | p.Glu14Ter | stop_gained, splice_region_variant | 1/5 | 1 | ENSP00000362214 | |||
TREM2 | ENST00000338469.3 | c.40G>T | p.Glu14Ter | stop_gained, splice_region_variant | 1/4 | 1 | ENSP00000342651 | |||
ENST00000702590.1 | n.364+7480C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 exome
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1
AN:
1461852
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Cov.:
32
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AC XY:
1
AN XY:
727228
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 17, 2019 | This variant is interpreted as Pathogenic for Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 , autosomal recessive. The following ACMG Tag(s) were applied: PM2, PS3, PVS1-Strong, PM3-Supporting. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at