rs386834142

Positions:

• chr6-41163036-ATCC-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_018965.4(TREM2):​c.40+4_40+6delGGA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TREM2 NM_018965.4 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.16

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]

ENSG00000290034 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-41163036-ATCC-A is Pathogenic according to our data. Variant chr6-41163036-ATCC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56723.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-41163036-ATCC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4	c.40+4_40+6delGGA		splice_region_variant, intron_variant		ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.40+4_40+6delGGA		splice_region_variant, intron_variant			NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8	c.40+4_40+6delGGA		splice_region_variant, intron_variant		1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122.8	c.40+4_40+6delGGA		splice_region_variant, intron_variant		1		ENSP00000362214.4
TREM2	ENST00000338469.3	c.40+4_40+6delGGA		splice_region_variant, intron_variant		1		ENSP00000342651.4
ENSG00000290034	ENST00000702590.1	n.364+7475_364+7477delCCT		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Mar 12, 2015	- -

Computational scores

Source: dbNSFP v4.3

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: rs386834142; hg19: chr6-41130774;