6-41158691-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The ENST00000338469.3(TREM2):c.572G>A(p.Trp191Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,028 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: TREM2 ENST00000338469.3 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.72

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.133 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 6-41158691-C-T is Benign according to our data. Variant chr6-41158691-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1575/152262) while in subpopulation AFR AF= 0.0349 (1451/41544). AF 95% confidence interval is 0.0334. There are 20 homozygotes in gnomad4. There are 724 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TREM2	NM_018965.4	c.*73G>A		3_prime_UTR_variant	5/5	ENST00000373113.8
TREM2	NM_001271821.2	c.572G>A	p.Trp191Ter	stop_gained	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TREM2	ENST00000338469.3	c.572G>A	p.Trp191Ter	stop_gained	4/4	1
TREM2	ENST00000373113.8	c.*73G>A		3_prime_UTR_variant	5/5	1	NM_018965.4	P1
TREM2	ENST00000373122.8	c.*137G>A		3_prime_UTR_variant	5/5	1
	ENST00000702590.1	n.364+3128C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1579 AN: 152144 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00306 AC: 768 AN: 250988 Hom.: 6 AF XY: 0.00243 AC XY: 329 AN XY: 135664

Gnomad AFR exome AF: 0.0387

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00114 AC: 1661 AN: 1461766 Hom.: 19 Cov.: 31 AF XY: 0.00101 AC XY: 738 AN XY: 727172

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.0103 AC: 1575 AN: 152262 Hom.: 20 Cov.: 32 AF XY: 0.00973 AC XY: 724 AN XY: 74438

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00544 Hom.: 6

Bravo AF: 0.0131

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0311 AC: 43

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.00353 AC: 429

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TREM2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 26, 2018

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.11
Dann	Benign	0.61
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0056	N
MutationTaster	Benign	0.90	D;N;N
Vest4		0.11
GERP RS		-2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2234258; hg19: chr6-41126429; COSMIC: COSV58294427; COSMIC: COSV58294427;