rs386834143

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

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.02
Variant links:
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
TREM2NM_018965.4 linkuse as main transcriptc.40G>T p.Glu14Ter stop_gained, splice_region_variant 1/5 ENST00000373113.8 NP_061838.1
TREM2NM_001271821.2 linkuse as main transcriptc.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
TREM2ENST00000373113.8 linkuse as main transcriptc.40G>T p.Glu14Ter stop_gained, splice_region_variant 1/51 NM_018965.4 ENSP00000362205 P1Q9NZC2-1
TREM2ENST00000373122.8 linkuse as main transcriptc.40G>T p.Glu14Ter stop_gained, splice_region_variant 1/51 ENSP00000362214 Q9NZC2-3
TREM2ENST00000338469.3 linkuse as main transcriptc.40G>T p.Glu14Ter stop_gained, splice_region_variant 1/41 ENSP00000342651 Q9NZC2-2
ENST00000702590.1 linkuse as main transcriptn.364+7480C>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727228
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
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 providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Pathogenic:1
Pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsOct 17, 2019This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
49
DANN
Uncertain
1.0
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.79
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.13
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386834143; hg19: chr6-41130781; API