NM_018965.4:c.469C>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.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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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=0.00671196).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM2	NM_018965.4 link	c.469C>T	p.His157Tyr	missense_variant	Exon 3 of 5	ENST00000373113.8	NP_061838.1	Q9NZC2-1Q5TCX1
TREM2	NM_001271821.2 link	c.469C>T	p.His157Tyr	missense_variant	Exon 3 of 4		NP_001258750.1	Q9NZC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TREM2	ENST00000373113.8 link	c.469C>T	p.His157Tyr	missense_variant	Exon 3 of 5	1	NM_018965.4	ENSP00000362205.3	Q9NZC2-1
TREM2	ENST00000373122.8 link	c.469C>T	p.His157Tyr	missense_variant	Exon 3 of 5	1		ENSP00000362214.4	Q9NZC2-3
TREM2	ENST00000338469.3 link	c.469C>T	p.His157Tyr	missense_variant	Exon 3 of 4	1		ENSP00000342651.4	Q9NZC2-2
ENSG00000290034	ENST00000702590.1 link	n.364+4242G>A		intron_variant	Intron 2 of 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

GnomAD3 exomes

AF:

0.00490

AC:

1233

AN:

251396

Hom.:

AF XY:

0.00364

AC XY:

495

AN XY:

135874

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 SAS exome

AF:

0.000719

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

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.0299

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.000856

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00189

AC:

287

AN:

152250

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.0153

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000732

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

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27501831, 28855301, 28855300, 28985224, 24899047, 27067662, 27084067, 23150934, 24119542) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

May 11, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

Benign:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.74

T;T;T

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.049

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.025

D;T;D

Polyphen

0.98

D;P;D

Vest4

0.37

MVP

0.63

MPC

0.41

ClinPred

0.030

GERP RS

3.8

Varity_R

0.11

gMVP

0.49

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