11-4600726-G-C

Position:

• chr11-4600726-G-C

Variant summary

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

The NM_018073.8(TRIM68):​c.1008C>G​(p.Asp336Glu) 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: TRIM68 NM_018073.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15722737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM68	NM_018073.8	c.1008C>G	p.Asp336Glu	missense_variant	7/7	ENST00000300747.10	NP_060543.5
TRIM68	NM_001304496.2	c.339C>G	p.Asp113Glu	missense_variant	6/6		NP_001291425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM68	ENST00000300747.10	c.1008C>G	p.Asp336Glu	missense_variant	7/7	1	NM_018073.8	ENSP00000300747	P1
TRIM68	ENST00000526337.5	c.339C>G	p.Asp113Glu	missense_variant	6/6	5		ENSP00000434681
TRIM68	ENST00000531101.5	c.*442C>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000431783

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 26, 2023

The c.1008C>G (p.D336E) alteration is located in exon 7 (coding exon 6) of the TRIM68 gene. This alteration results from a C to G substitution at nucleotide position 1008, causing the aspartic acid (D) at amino acid position 336 to be replaced by a glutamic acid (E). 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	0.33
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	0.047
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.67	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N;D
REVEL	Benign	0.10
Sift	Benign	0.51	T;D
Sift4G	Benign	0.16	T;D
Polyphen		0.96	D;.
Vest4		0.078
MutPred		0.36		Gain of methylation at K333 (P = 0.0878);.;
MVP		0.55
MPC		0.18
ClinPred		0.40	T
GERP RS		2.5
Varity_R		0.046
gMVP		0.24

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: rs1846474617; hg19: chr11-4621956;