rs2234253

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The ENST00000373113.8(TREM2):c.287C>T(p.Thr96Met) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T96K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

TREM2
ENST00000373113.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 5.77

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00063 (96/152318) while in subpopulation AFR AF= 0.00209 (87/41550). AF 95% confidence interval is 0.00174. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4 linkuse as main transcript	c.287C>T	p.Thr96Met	missense_variant	2/5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2 linkuse as main transcript	c.287C>T	p.Thr96Met	missense_variant	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.287C>T	p.Thr96Met	missense_variant	2/5	1	NM_018965.4	ENSP00000362205	P1	Q9NZC2-1
TREM2	ENST00000373122.8 linkuse as main transcript	c.287C>T	p.Thr96Met	missense_variant	2/5	1		ENSP00000362214		Q9NZC2-3
TREM2	ENST00000338469.3 linkuse as main transcript	c.287C>T	p.Thr96Met	missense_variant	2/4	1		ENSP00000342651		Q9NZC2-2
	ENST00000702590.1 linkuse as main transcript	n.364+5804G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251476

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000630

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000946

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 96 of the TREM2 protein (p.Thr96Met). This variant is present in population databases (rs2234253, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TREM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1448028). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TREM2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.65

D;D;D

MetaSVM

Uncertain

0.042

MutationAssessor

Pathogenic

3.5

M;M;M

MutationTaster

Benign

0.0028

P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.85

MutPred

0.36

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.75

MPC

0.66

ClinPred

0.17

GERP RS

5.5

Varity_R

0.66

gMVP

0.47

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

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