rs104894002

Positions:

chr6-41161557-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The ENST00000373113.8(TREM2):c.97C>T(p.Gln33Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TREM2
ENST00000373113.8 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 1.17

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]

TREM2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 15 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-41161557-G-A is Pathogenic according to our data. Variant chr6-41161557-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41161557-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4 linkuse as main transcript	c.97C>T	p.Gln33Ter	stop_gained	2/5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2 linkuse as main transcript	c.97C>T	p.Gln33Ter	stop_gained	2/4		NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8 linkuse as main transcript	c.97C>T	p.Gln33Ter	stop_gained	2/5	1	NM_018965.4	ENSP00000362205	P1	Q9NZC2-1
TREM2	ENST00000373122.8 linkuse as main transcript	c.97C>T	p.Gln33Ter	stop_gained	2/5	1		ENSP00000362214		Q9NZC2-3
TREM2	ENST00000338469.3 linkuse as main transcript	c.97C>T	p.Gln33Ter	stop_gained	2/4	1		ENSP00000342651		Q9NZC2-2
	ENST00000702590.1 linkuse as main transcript	n.364+5994G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

248072

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000451

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000441

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 14, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	This variant has been reported to cause a PLOSL with typical bone pathology on radiologic examination but also a frontotemporal dementia-like syndrome without bone pathology on radiographs. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

Pathogenic:2

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, PP1, PM3, PS3, PVS1-Strong. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 10, 2005	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

The c.97C>T (p.Q33*) alteration, located in exon 2 (coding exon 2) of the TREM2 gene, consists of a C to T substitution at nucleotide position 97. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 33. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/248072) total alleles studied. The highest observed frequency was 0.005% (5/110958) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state in multiple unrelated individuals with TREM2-related polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. It has also been found to cosegregate among affected homozygous siblings (Coomans, 2018; Guerreiro, 2013; Bock, 2013; Soragna, 2003). Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 21, 2022

This sequence change creates a premature translational stop signal (p.Gln33*) in the TREM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TREM2 are known to be pathogenic (PMID: 12080485, 12754369, 12883936, 12925681, 23318515, 23582655). This variant is present in population databases (rs104894002, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive TREM2-related conditions (PMID: 12754369, 23318515). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5219). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TREM2 function (PMID: 25615530). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.18

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.029

MutationTaster

Benign

1.0

A;A;A

Vest4

0.80

GERP RS

-0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over