Genetic Variant NM_018965.4:c.401A>C (chr6-41159873-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_018965.4(TREM2):c.401A>C(p.Asp134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D134G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TREM2
NM_018965.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.503

Publications

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

TREM2 links:

ENSG00000290034 (HGNC:):

ENSG00000290034 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-41159873-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5215.

BP4

Computational evidence support a benign effect (MetaRNN=0.27206093).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREM2	NM_018965.4	MANE Select	c.401A>C	p.Asp134Ala	missense	Exon 3 of 5	NP_061838.1
	TREM2	NM_001271821.2		c.401A>C	p.Asp134Ala	missense	Exon 3 of 4	NP_001258750.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TREM2	ENST00000373113.8	TSL:1 MANE Select	c.401A>C	p.Asp134Ala	missense	Exon 3 of 5	ENSP00000362205.3
TREM2	ENST00000373122.8	TSL:1	c.401A>C	p.Asp134Ala	missense	Exon 3 of 5	ENSP00000362214.4
TREM2	ENST00000338469.3	TSL:1	c.401A>C	p.Asp134Ala	missense	Exon 3 of 4	ENSP00000342651.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.65

M_CAP

Benign

0.0095

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

0.50

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.50

REVEL

Benign

0.14

Sift

Benign

0.067

Sift4G

Uncertain

0.014

Polyphen

0.97

Vest4

0.27

MutPred

0.70

Gain of sheet (P = 0.0011)

MVP

0.52

MPC

0.25

ClinPred

0.36

GERP RS

3.3

Varity_R

0.078

gMVP

0.56

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over