11-4600486-C-A

Position:

• chr11-4600486-C-A

Variant summary

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

The NM_018073.8(TRIM68):​c.1248G>T​(p.Leu416Phe) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM68 NM_018073.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

TRIM68 (HGNC:21161): (tripartite motif containing 68) This gene encodes a member of the tripartite motif-containing protein family, whose members are characterized by a "really interesting new gene" (RING) finger domain, a zinc-binding B-box motif, and a coiled-coil region. Members of this family function as E3 ubiquitin ligases and are involved in a broad range of biological processes. This gene regulates the activation of nuclear receptors, such as androgen receptor, and has been implicated in development of prostate cancer cells, where its expression increases in response to a downregulation of microRNAs. In addition, this gene participates in viral defense regulation as a negative regulator of interferon-beta. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

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=0.2834303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM68	NM_018073.8	c.1248G>T	p.Leu416Phe	missense_variant	7/7	ENST00000300747.10	NP_060543.5
TRIM68	NM_001304496.2	c.579G>T	p.Leu193Phe	missense_variant	6/6		NP_001291425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM68	ENST00000300747.10	c.1248G>T	p.Leu416Phe	missense_variant	7/7	1	NM_018073.8	ENSP00000300747	P1
TRIM68	ENST00000531101.5	c.*682G>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000431783

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

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

Jun 30, 2022

The c.1248G>T (p.L416F) alteration is located in exon 7 (coding exon 6) of the TRIM68 gene. This alteration results from a G to T substitution at nucleotide position 1248, causing the leucine (L) at amino acid position 416 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.00075	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.00080	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.72	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.45		Loss of catalytic residue at L416 (P = 0.0842);
MVP		0.74
MPC		0.45
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.37

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: chr11-4621716;