6-41236540-G-T

Variant names:

• chr6-41236540-G-T
• NM_198153.3:c.561G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198153.3(TREML4):​c.561G>T​(p.Leu187Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TREML4 NM_198153.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.850

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052414358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREML4	NM_198153.3	c.561G>T	p.Leu187Phe	missense_variant	Exon 5 of 6	ENST00000341495.7	NP_937796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREML4	ENST00000341495.7	c.561G>T	p.Leu187Phe	missense_variant	Exon 5 of 6	1	NM_198153.3	ENSP00000342570.2
TREML4	ENST00000448827.6	c.561G>T	p.Leu187Phe	missense_variant	Exon 5 of 6	1		ENSP00000418078.1
TREML4	ENST00000461240.1	n.*184G>T		non_coding_transcript_exon_variant	Exon 5 of 6	2		ENSP00000418480.1
TREML4	ENST00000461240.1	n.*184G>T		3_prime_UTR_variant	Exon 5 of 6	2		ENSP00000418480.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.561G>T (p.L187F) alteration is located in exon 5 (coding exon 5) of the TREML4 gene. This alteration results from a G to T substitution at nucleotide position 561, causing the leucine (L) at amino acid position 187 to be replaced by a phenylalanine (F). 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	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.12
DANN	Benign	0.34
DEOGEN2	Benign	0.0050	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.18	.;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.039
Sift	Benign	0.22	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0	B;B
Vest4		0.049
MutPred		0.55		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.014
MPC		0.031
ClinPred		0.074	T
GERP RS		-4.8
Varity_R		0.043
gMVP		0.082

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41204278;