chr6-41229521-C-T

Variant names:

• chr6-41229521-C-T
• rs200401569
• NM_198153.3:c.395C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198153.3(TREML4):​c.395C>T​(p.Ala132Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TREML4 NM_198153.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003631
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097581506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREML4	NM_198153.3	c.395C>T	p.Ala132Val	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000341495.7	NP_937796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREML4	ENST00000341495.7	c.395C>T	p.Ala132Val	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_198153.3	ENSP00000342570.2
TREML4	ENST00000448827.6	c.395C>T	p.Ala132Val	missense_variant, splice_region_variant	Exon 3 of 6	1		ENSP00000418078.1
TREML4	ENST00000461240.1	n.89C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 6	2		ENSP00000418480.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395C>T (p.A132V) alteration is located in exon 3 (coding exon 3) of the TREML4 gene. This alteration results from a C to T substitution at nucleotide position 395, causing the alanine (A) at amino acid position 132 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.1
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.46	.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.46	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.027
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.85	P;P
Vest4		0.19
MutPred		0.40		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.030
MPC		0.083
ClinPred		0.27	T
GERP RS		0.97
Varity_R		0.071
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.062
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: rs200401569; hg19: chr6-41197259;