chr7-28955825-A-G

Variant names:

• chr7-28955825-A-G
• rs1360115666
• NM_014817.4:c.2222T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014817.4(TRIL):​c.2222T>C​(p.Met741Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,397,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: TRIL NM_014817.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26894185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIL	NM_014817.4	c.2222T>C	p.Met741Thr	missense_variant	Exon 1 of 1	ENST00000539664.3	NP_055632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIL	ENST00000539664.3	c.2222T>C	p.Met741Thr	missense_variant	Exon 1 of 1	6	NM_014817.4	ENSP00000479256.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1397554 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689284

African (AFR) AF: 0.00 AC: 0 AN: 31574

American (AMR) AF: 0.00 AC: 0 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1078718

Other (OTH) AF: 0.00 AC: 0 AN: 57942

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2222T>C (p.M741T) alteration is located in exon 1 (coding exon 1) of the TRIL gene. This alteration results from a T to C substitution at nucleotide position 2222, causing the methionine (M) at amino acid position 741 to be replaced by a threonine (T). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Benign	0.87
DEOGEN2	Benign	0.035	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.27	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.90	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.92	P
Vest4		0.34
MVP		0.17
GERP RS		4.8
Varity_R		0.57
gMVP		0.70

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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Other links and lift over

dbSNP: rs1360115666; hg19: chr7-28995441;