NM_018965.4:c.469C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018965.4(TREM2):c.469C>T(p.His157Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,056 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H157H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 26 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.46

Publications

127 publications found

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 Gene-Disease associations (from GenCC):

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TREM2 links:

ENSG00000290034 (HGNC:):

ENSG00000290034 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00671196).

BP6

Variant 6-41159805-G-A is Benign according to our data. Variant chr6-41159805-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00189 (287/152250) while in subpopulation AMR AF = 0.0153 (234/15298). AF 95% confidence interval is 0.0137. There are 1 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018965.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREM2	NM_018965.4	MANE Select	c.469C>T	p.His157Tyr	missense	Exon 3 of 5	NP_061838.1	Q5TCX1
	TREM2	NM_001271821.2		c.469C>T	p.His157Tyr	missense	Exon 3 of 4	NP_001258750.1	Q9NZC2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TREM2	ENST00000373113.8	TSL:1 MANE Select	c.469C>T	p.His157Tyr	missense	Exon 3 of 5	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122.8	TSL:1	c.469C>T	p.His157Tyr	missense	Exon 3 of 5	ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3	TSL:1	c.469C>T	p.His157Tyr	missense	Exon 3 of 4	ENSP00000342651.4	Q9NZC2-2

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00490

AC:

1233

AN:

251396

AF XY:

0.00364

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0322

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00117

AC:

1707

AN:

1461806

Hom.:

Cov.:

AF XY:

0.000972

AC XY:

707

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.0299

AC:

1339

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26136

East Asian (EAS)

AF:

0.000856

AC:

AN:

39698

South Asian (SAS)

AF:

0.000499

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000158

AC:

176

AN:

1111948

Other (OTH)

AF:

0.00123

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00189

AC:

287

AN:

152250

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41534

American (AMR)

AF:

0.0153

AC:

234

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00213

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.00356

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00360

AC:

437

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

2.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

REVEL

Benign

0.049

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.025

Polyphen

0.98

Vest4

0.37

MVP

0.63

MPC

0.41

ClinPred

0.030

GERP RS

3.8

Varity_R

0.11

gMVP

0.49

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over