6-41161514-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018965.4(TREM2):c.140G>A(p.Arg47His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,154 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 13 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.99

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=0.012806624).

BP6

Variant 6-41161514-C-T is Benign according to our data. Variant chr6-41161514-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41161514-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.002 (304/152342) while in subpopulation AMR AF= 0.00477 (73/15312). AF 95% confidence interval is 0.00389. There are 1 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 4		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TREM2	ENST00000373113.8 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122.8 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 5	1		ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 4	1		ENSP00000342651.4	Q9NZC2-2
ENSG00000290034	ENST00000702590.1 link	n.364+5951C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00260

AC:

650

AN:

249752

Hom.:

AF XY:

0.00260

AC XY:

351

AN XY:

135068

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.00339

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00286

AC:

4174

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

2112

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00340

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00250

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00330

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152342

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

166

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00213

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00273

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 14, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 05, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29411406, 25585992, 25027412, 31836585, 24535663, 26365049, 31381512, 31513029, 29794134, 30222607, 29321225, 29557178, 28149270, 28430856, 29395285, 29859094, 28789839, 29525180, 27196974, 25160042, 27887626, 25936935, 23150908, 24990881, 25615530, 24663666, 24508568, 25186855, 25042114, 24119542, 24041969, 23582655, 23391427, 25886450, 23800361, 23380991, 26021840, 24899047, 28714976, 23855982, 26058841, 23150934, 26754641, 27589997) -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TREM2: BP4, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 23, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

Benign:1

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TREM2-related disorder

Benign:1

Jun 14, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

0.19

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.079

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.9

M;M;M

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.026

D;T;T

Sift4G

Uncertain

0.043

D;T;D

Polyphen

1.0

D;D;D

Vest4

0.40

MVP

0.64

MPC

0.71

ClinPred

0.052

GERP RS

4.6

Varity_R

0.25

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