6-41161277-A-C

Position:

• chr6-41161277-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_018965.4(TREM2):​c.377T>G​(p.Val126Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TREM2 NM_018965.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.37

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 6-41161277-A-C is Pathogenic according to our data. Variant chr6-41161277-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-41161277-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREM2	NM_018965.4	c.377T>G	p.Val126Gly	missense_variant	2/5	ENST00000373113.8	NP_061838.1
TREM2	NM_001271821.2	c.377T>G	p.Val126Gly	missense_variant	2/4		NP_001258750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREM2	ENST00000373113.8	c.377T>G	p.Val126Gly	missense_variant	2/5	1	NM_018965.4	ENSP00000362205.3
TREM2	ENST00000373122.8	c.377T>G	p.Val126Gly	missense_variant	2/5	1		ENSP00000362214.4
TREM2	ENST00000338469.3	c.377T>G	p.Val126Gly	missense_variant	2/4	1		ENSP00000342651.4
ENSG00000290034	ENST00000702590.1	n.364+5714A>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250904 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461628 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 10, 2005	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 17, 2019	This variant is interpreted as Likely pathogenic for Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 , autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PM3, PS3. -

TREM2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2022

The TREM2 c.377T>G variant is predicted to result in the amino acid substitution p.Val126Gly. This variant has been reported in individuals with Nasu-Hakola disease, also referred to as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Klünemann et al 2005. PubMed ID: 15883308; Lynch DS et al 2017. PubMed ID: 28334938). Functional studies showed the p.Val126Gly change disrupts TREM2 trafficking to the cell membrane and impairs function (Sirkis DW et al 2017. PubMed ID: 28768830; Kober DL et al 2016. PubMed ID: 27995897). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-41129015-A-C).This variant is interpreted as pathogenic. -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.70		Loss of helix (P = 3e-04);Loss of helix (P = 3e-04);Loss of helix (P = 3e-04);
MVP		0.70
MPC		0.74
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121908402; hg19: chr6-41129015;