6-41276197-A-G

Variant names:

• chr6-41276197-A-G
• rs2234244
• ENST00000334475.10:c.440T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001242590.3(TREM1):​c.440T>C​(p.Leu147Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,138 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (7 hom.)
• Consequence: TREM1 NM_001242590.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.286

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024181008).
• BP6: Variant 6-41276197-A-G is Benign according to our data. Variant chr6-41276197-A-G is described in ClinVar as [Benign]. Clinvar id is 768089.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00657 (1000/152268) while in subpopulation AFR AF= 0.0217 (902/41546). AF 95% confidence interval is 0.0205. There are 16 homozygotes in gnomad4. There are 468 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREM1	NM_018643.5	c.633T>C	p.Ala211Ala	synonymous_variant	Exon 4 of 4	ENST00000244709.9	NP_061113.1
TREM1	NM_001242590.3	c.440T>C	p.Leu147Pro	missense_variant	Exon 3 of 3		NP_001229519.1
TREM1	XM_011514696.3	c.599+4764T>C		intron_variant	Intron 3 of 3		XP_011512998.1
TREM1	NR_136332.2	n.660T>C		non_coding_transcript_exon_variant	Exon 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREM1	ENST00000334475.10	c.440T>C	p.Leu147Pro	missense_variant	Exon 3 of 3	1		ENSP00000334284.5
TREM1	ENST00000244709.9	c.633T>C	p.Ala211Ala	synonymous_variant	Exon 4 of 4	1	NM_018643.5	ENSP00000244709.3
TREM1	ENST00000589614.5	c.599+4764T>C		intron_variant	Intron 3 of 3	2		ENSP00000465688.1
TREM1	ENST00000589695.1	n.308T>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 995 AN: 152150 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00166 AC: 417 AN: 251420 Hom.: 5 AF XY: 0.00122 AC XY: 166 AN XY: 135874

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000832 AC: 1217 AN: 1461870 Hom.: 7 Cov.: 31 AF XY: 0.000776 AC XY: 564 AN XY: 727240

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00657 AC: 1000 AN: 152268 Hom.: 16 Cov.: 32 AF XY: 0.00629 AC XY: 468 AN XY: 74456

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00354 Hom.: 1

Bravo AF: 0.00764

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 09, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.2
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.94	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.044
MVP		0.048
ClinPred		0.0052	T
GERP RS		-2.2

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: rs2234244; hg19: chr6-41243935;