4-188146857-T-C

Variant summary

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

The NM_178556.5(TRIML1):c.892T>C(p.Tyr298His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,289,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TRIML1 NM_178556.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.46

Genes affected

TRIML1 (HGNC:26698): (tripartite motif family like 1) The protein encoded by this gene is a tripartite motif family protein with similarities to E3 ubiquitin-protein ligases. While the function of the encoded protein has not been determined, the orthologous protein in mouse has been shown to bind ubiquitin-specific protease 5 and is involved in the blastocyst development stage. [provided by RefSeq, Sep 2016]

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=0.07636526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIML1	NM_178556.5	c.892T>C	p.Tyr298His	missense_variant	6/6	ENST00000332517.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIML1	ENST00000332517.4	c.892T>C	p.Tyr298His	missense_variant	6/6	1	NM_178556.5	P1
TRIML1	ENST00000507581.5	n.352T>C		non_coding_transcript_exon_variant	3/3	1
TRIML1	ENST00000512233.1	n.242T>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1289116 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 625290

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.75e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000354 Hom.: 0

Bravo AF: 0.00000756

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 15, 2021

The c.892T>C (p.Y298H) alteration is located in exon 6 (coding exon 6) of the TRIML1 gene. This alteration results from a T to C substitution at nucleotide position 892, causing the tyrosine (Y) at amino acid position 298 to be replaced by a histidine (H). 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	0.48
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.084	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.056
Sift	Benign	0.43	T
Sift4G	Benign	0.45	T
Polyphen		0.0040	B
Vest4		0.20
MVP		0.014
MPC		0.047
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.049
gMVP		0.34

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: rs1242967850; hg19: chr4-189068011;