6-41282397-T-G

Variant summary

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

The NM_018643.5(TREM1):c.404A>C(p.Lys135Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,605,342 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (13 hom.)
• Consequence: TREM1 NM_018643.5 missense, splice_region
• Scores: Splicing: ADA: 0.00004585
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.822

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=0.0058051646).
• BP6: Variant 6-41282397-T-G is Benign according to our data. Variant chr6-41282397-T-G is described in ClinVar as [Benign]. Clinvar id is 723369.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00644 (980/152214) while in subpopulation AFR AF= 0.0223 (928/41574). AF 95% confidence interval is 0.0211. There are 7 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TREM1	NM_018643.5	c.404A>C	p.Lys135Thr	missense_variant, splice_region_variant	2/4	ENST00000244709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TREM1	ENST00000244709.9	c.404A>C	p.Lys135Thr	missense_variant, splice_region_variant	2/4	1	NM_018643.5	P2

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 973 AN: 152096 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00175 AC: 432 AN: 246894 Hom.: 6 AF XY: 0.00128 AC XY: 170 AN XY: 133272

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000630 AC: 916 AN: 1453128 Hom.: 13 Cov.: 30 AF XY: 0.000535 AC XY: 386 AN XY: 721796

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.0000136

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00644 AC: 980 AN: 152214 Hom.: 7 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74408

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00113 Hom.: 3

Bravo AF: 0.00746

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	12
Dann	Benign	0.97
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.72	T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.58, 0.71	.;P;P;.
Vest4		0.26
MVP		0.15
MPC		0.27
ClinPred		0.020	T
GERP RS		-2.7
Varity_R		0.43
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs34727391; hg19: chr6-41250135; COSMIC: COSV99044298; COSMIC: COSV99044298;