11-8621707-G-C

Position:

• chr11-8621707-G-C

Variant summary

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

The NM_001388022.1(TRIM66):​c.3193C>G​(p.Gln1065Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000786 in 1,399,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: TRIM66 NM_001388022.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

Genes affected

TRIM66 (HGNC:29005): (tripartite motif containing 66) Predicted to enable chromatin binding activity and identical protein binding activity. Predicted to act upstream of or within negative regulation of transcription, DNA-templated. Located in aggresome and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRIM66 (HGNC:):

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=0.20509306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM66	NM_001388022.1	c.3193C>G	p.Gln1065Glu	missense_variant	19/25	ENST00000646038.2	NP_001374951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM66	ENST00000646038.2	c.3193C>G	p.Gln1065Glu	missense_variant	19/25		NM_001388022.1	ENSP00000495413.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1399424 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 690208

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000861

GnomAD4 genome Cov.: 31

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

Jan 26, 2022

The c.2665C>G (p.Q889E) alteration is located in exon 14 (coding exon 13) of the TRIM66 gene. This alteration results from a C to G substitution at nucleotide position 2665, causing the glutamine (Q) at amino acid position 889 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	0.063
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0020	T;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.52	D;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.50	N;N;.
REVEL	Benign	0.041
Sift	Benign	0.31	T;T;.
Sift4G	Benign	0.60	T;T;.
Polyphen		0.14	B;.;.
Vest4		0.28
MutPred		0.29		Gain of ubiquitination at K886 (P = 0.0898);.;.;
MVP		0.44
ClinPred		0.68	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1396355494; hg19: chr11-8643254;