6-41276204-A-G

Variant names:

• chr6-41276204-A-G
• NM_018643.5:c.626T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_018643.5(TREM1):​c.626T>C​(p.Leu209Pro) 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 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TREM1 NM_018643.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.157
• Publications: 0 publications found

Genes affected

TREM1 (HGNC:17760): (triggering receptor expressed on myeloid cells 1) This gene encodes a receptor belonging to the Ig superfamily that is expressed on myeloid cells. This protein amplifies neutrophil and monocyte-mediated inflammatory responses triggered by bacterial and fungal infections by stimulating release of pro-inflammatory chemokines and cytokines, as well as increased surface expression of cell activation markers. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098330736).
• BP6: Variant 6-41276204-A-G is Benign according to our data. Variant chr6-41276204-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2681620.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018643.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREM1	NM_018643.5	MANE Select	c.626T>C	p.Leu209Pro	missense	Exon 4 of 4	NP_061113.1	Q38L15
	TREM1	NM_001242590.3		c.433T>C	p.Ser145Pro	missense	Exon 3 of 3	NP_001229519.1	Q9NP99-2
	TREM1	NR_136332.2		n.653T>C		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREM1	ENST00000244709.9	TSL:1 MANE Select	c.626T>C	p.Leu209Pro	missense	Exon 4 of 4	ENSP00000244709.3	Q9NP99-1
	TREM1	ENST00000334475.11	TSL:1	c.433T>C	p.Ser145Pro	missense	Exon 3 of 3	ENSP00000334284.5	Q9NP99-2
	TREM1	ENST00000589614.6	TSL:2	c.599+4757T>C		intron	N/A	ENSP00000465688.1	K7EKM5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EBV-positive nodal T- and NK-cell lymphoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.16
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.82	N
REVEL	Benign	0.053
Sift	Benign	0.081	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.62		Loss of sheet (P = 0.0037)
MVP		0.14
MPC		0.16
ClinPred		0.42	T
GERP RS		-3.1
Varity_R		0.082
gMVP		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr6-41243942;