7-28956050-C-T

Position:

• chr7-28956050-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.598

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TRIL	NM_014817.4	c.1997G>A	p.Gly666Glu	missense_variant	1/1	ENST00000539664.3	NP_055632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIL	ENST00000539664.3	c.1997G>A	p.Gly666Glu	missense_variant	1/1		NM_014817.4	ENSP00000479256	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152244 Hom.: 0 Cov.: 34

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

GnomAD3 exomes AF: 0.000349 AC: 51 AN: 146198 Hom.: 0 AF XY: 0.000463 AC XY: 37 AN XY: 79882

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 SAS exome AF: 0.00157

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.: 2 Cov.: 30 AF XY: 0.000224 AC XY: 155 AN XY: 690618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000109

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000987

Gnomad4 OTH exome AF: 0.000394

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152362 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000213 AC: 24

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

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	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.074	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.020	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.16	B
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

LitVar

Other links and lift over

dbSNP: rs562686571; hg19: chr7-28995666;