Genetic Variant TREML4:p.Ile83Met (chr6-41228899-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198153.3(TREML4):c.249C>G(p.Ile83Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

TREML4
NM_198153.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.443

Variant links:

Genes affected

TREML4 (HGNC:30807): (triggering receptor expressed on myeloid cells like 4) Predicted to enable signaling receptor activity. Involved in positive regulation of toll-like receptor 7 signaling pathway. Predicted to be located in endoplasmic reticulum. Predicted to be active in cell surface. Predicted to colocalize with endosome membrane and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TREML4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREML4	NM_198153.3 link	c.249C>G	p.Ile83Met	missense_variant	Exon 2 of 6	ENST00000341495.7	NP_937796.1	Q6UXN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TREML4	ENST00000341495.7 link	c.249C>G	p.Ile83Met	missense_variant	Exon 2 of 6	1	NM_198153.3	ENSP00000342570.2	Q6UXN2
TREML4	ENST00000448827.6 link	c.249C>G	p.Ile83Met	missense_variant	Exon 2 of 6	1		ENSP00000418078.1	Q6UXN2
TREML4	ENST00000461240.1 link	n.-58C>G		upstream_gene_variant		2		ENSP00000418480.1	H7C4X5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.249C>G (p.I83M) alteration is located in exon 2 (coding exon 2) of the TREML4 gene. This alteration results from a C to G substitution at nucleotide position 249, causing the isoleucine (I) at amino acid position 83 to be replaced by a methionine (M). 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

Benign

0.32

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

0.13

Eigen_PC

Benign

-0.073

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.41

.;T

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0050

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.41

MutPred

0.78

Gain of ubiquitination at K86 (P = 0.0686);Gain of ubiquitination at K86 (P = 0.0686);

MVP

0.23

MPC

0.23

ClinPred

0.78

GERP RS

1.6

Varity_R

0.31

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over