7-99892208-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033091.3(TRIM4):c.1380T>G(p.Ser460Arg) variant causes a missense 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. 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)
• Consequence: TRIM4 NM_033091.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0940

Genes affected

TRIM4 (HGNC:16275): (tripartite motif containing 4) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. Its function has not been identified. Alternatively spliced transcript variants that encode different isoforms have been described.[provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33945942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM4	NM_033091.3	c.1380T>G	p.Ser460Arg	missense_variant	6/6	ENST00000349062.7
TRIM4	NM_033017.4	c.1458T>G	p.Ser486Arg	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM4	ENST00000349062.7	c.1380T>G	p.Ser460Arg	missense_variant	6/6	1	NM_033091.3	P2
TRIM4	ENST00000355947.6	c.1458T>G	p.Ser486Arg	missense_variant	7/7	1		A2
TRIM4	ENST00000447480.5	c.545+11010T>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Dec 15, 2022

The c.1458T>G (p.S486R) alteration is located in exon 7 (coding exon 7) of the TRIM4 gene. This alteration results from a T to G substitution at nucleotide position 1458, causing the serine (S) at amino acid position 486 to be replaced by an arginine (R). 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	0.93
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.073	T;T
Sift4G	Benign	0.064	T;T
Polyphen		0.96	D;P
Vest4		0.41
MutPred		0.65		Gain of glycosylation at S490 (P = 0.1579);.;
MVP		0.45
MPC		0.84
ClinPred		0.75	D
GERP RS		1.4
Varity_R		0.11
gMVP		0.71

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: chr7-99489831;