6-41161367-G-T

Position:

chr6-41161367-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018965.4(TREM2):c.287C>A(p.Thr96Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00728 in 1,614,204 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T96R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.036 ( 317 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 306 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

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:

ENSG00000290034 (HGNC:):

ENSG00000290034 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032537878).

BP6

Variant 6-41161367-G-T is Benign according to our data. Variant chr6-41161367-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 356678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41161367-G-T is described in Lovd as [Benign]. Variant chr6-41161367-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/4		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TREM2	ENST00000373113.8 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122.8 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/5	1		ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/4	1		ENSP00000342651.4	Q9NZC2-2
ENSG00000290034	ENST00000702590.1 linkuse as main transcript	n.364+5804G>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5477

AN:

152192

Hom.:

320

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.00996

AC:

2504

AN:

251476

Hom.:

155

AF XY:

0.00776

AC XY:

1055

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00775

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00429

AC:

6269

AN:

1461894

Hom.:

306

Cov.:

AF XY:

0.00386

AC XY:

2805

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.127

Gnomad4 AMR exome

AF:

0.00890

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000840

Gnomad4 OTH exome

AF:

0.00881

GnomAD4 genome

AF:

0.0360

AC:

5480

AN:

152310

Hom.:

317

Cov.:

AF XY:

0.0346

AC XY:

2574

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.0166

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.00456

Hom.:

Bravo

AF:

0.0424

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.113

AC:

500

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0120

AC:

1457

EpiCase

AF:

0.000927

EpiControl

AF:

0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2020	This variant is associated with the following publications: (PMID: 25042114, 28430856, 28789839, 29723869) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.1

M;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.35

MPC

0.71

ClinPred

0.044

GERP RS

5.5

Varity_R

0.83

gMVP

0.59

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