Genetic Variant TRIL:p.Gly666Glu (chr7-28956050-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014817.4(TRIL):c.1997G>A(p.Gly666Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,550,120 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G666R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

TRIL
NM_014817.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.598

Variant links:

Genes affected

TRIL (HGNC:22200): (TLR4 interactor with leucine rich repeats) TRIL is a component of the TLR4 (MIM 603030) complex and is induced in a number of cell types by lipopolysaccharide (LPS) (Carpenter et al., 2009 [PubMed 19710467]).[supplied by OMIM, Apr 2010]

TRIL links:

CPVL-AS2 (HGNC:56138): (CPVL antisense RNA 2)

CPVL-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020411104).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIL	NM_014817.4 link	c.1997G>A	p.Gly666Glu	missense_variant	Exon 1 of 1	ENST00000539664.3	NP_055632.2	Q7L0X0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIL	ENST00000539664.3 link	c.1997G>A	p.Gly666Glu	missense_variant	Exon 1 of 1	6	NM_014817.4	ENSP00000479256.1		Q7L0X0

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000349

AC:

AN:

146198

AF XY:

0.000463

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000789

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.000691

GnomAD4 exome

AF:

0.000183

AC:

256

AN:

1397758

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

155

AN XY:

690618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31920

American (AMR)

AF:

0.000109

AC:

AN:

36678

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25240

East Asian (EAS)

AF:

0.00

AC:

AN:

36192

South Asian (SAS)

AF:

0.00143

AC:

114

AN:

79710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40170

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.0000987

AC:

107

AN:

1083846

Other (OTH)

AF:

0.000394

AC:

AN:

58324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000144

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41592

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000213

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1997G>A (p.G666E) alteration is located in exon 1 (coding exon 1) of the TRIL gene. This alteration results from a G to A substitution at nucleotide position 1997, causing the glycine (G) at amino acid position 666 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.074

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

MetaRNN

Benign

0.020

MutationAssessor

Benign

0.81

PhyloP100

0.60

PrimateAI

Pathogenic

0.91

Sift4G

Pathogenic

0.0

Polyphen

0.16

Vest4

0.28

MVP

0.24

GERP RS

3.2

Varity_R

0.17

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

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

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7-28956050-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over