rs142232675

Positions:

• chr6-41161395-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018965.4(TREM2):​c.259G>A​(p.Asp87Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,614,234 control chromosomes in the GnomAD database, including 5 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (2 hom.)
• Consequence: TREM2 NM_018965.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.04

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]

ENSG00000290034 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017710984).
• BP6: Variant 6-41161395-C-T is Benign according to our data. Variant chr6-41161395-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261064.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}. Variant chr6-41161395-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00144 (219/152340) while in subpopulation NFE AF= 0.00284 (193/68034). AF 95% confidence interval is 0.00251. There are 3 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4	c.259G>A	p.Asp87Asn	missense_variant	2/5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.259G>A	p.Asp87Asn	missense_variant	2/4		NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8	c.259G>A	p.Asp87Asn	missense_variant	2/5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122.8	c.259G>A	p.Asp87Asn	missense_variant	2/5	1		ENSP00000362214.4
TREM2	ENST00000338469.3	c.259G>A	p.Asp87Asn	missense_variant	2/4	1		ENSP00000342651.4
ENSG00000290034	ENST00000702590.1	n.364+5832C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000970 AC: 244 AN: 251484 Hom.: 0 AF XY: 0.000927 AC XY: 126 AN XY: 135912

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000938 AC: 1371 AN: 1461894 Hom.: 2 Cov.: 32 AF XY: 0.000953 AC XY: 693 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74490

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00172 Hom.: 1

Bravo AF: 0.000967

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TREM2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	This variant is associated with the following publications: (PMID: 30530974, 30883352, 30106757, 30033062, 29557178, 26754641, 27589997, 23150934, 24119542, 25886450, 31836585) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;.
Eigen	Benign	0.089
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.20
MVP		0.46
MPC		0.64
ClinPred		0.054	T
GERP RS		5.5
Varity_R		0.34
gMVP		0.46

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

Other links and lift over

dbSNP: rs142232675; hg19: chr6-41129133; COSMIC: COSV58294913;