11-8620069-T-C

Variant names:

• chr11-8620069-T-C
• rs2034059727
• NM_001388022.1:c.3728A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001388022.1(TRIM66):​c.3728A>G​(p.His1243Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: TRIM66 NM_001388022.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4228195).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388022.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM66	NM_001388022.1	MANE Select	c.3728A>G	p.His1243Arg	missense	Exon 22 of 25	NP_001374951.1	A0A8Z5E822
	TRIM66	NM_001388024.1		c.3644A>G	p.His1215Arg	missense	Exon 23 of 26	NP_001374953.1
	TRIM66	NM_001388023.1		c.3617A>G	p.His1206Arg	missense	Exon 22 of 25	NP_001374952.1	A0A994J572

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM66	ENST00000646038.2	MANE Select	c.3728A>G	p.His1243Arg	missense	Exon 22 of 25	ENSP00000495413.1	A0A8Z5E822
	TRIM66	ENST00000705689.1		c.3617A>G	p.His1206Arg	missense	Exon 22 of 25	ENSP00000516162.1	A0A994J572
	TRIM66	ENST00000705690.1		c.3293A>G	p.His1098Arg	missense	Exon 17 of 20	ENSP00000516163.1	A0A994J7V7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399452 Hom.: 0 Cov.: 32 AF XY: 0.00000580 AC XY: 4 AN XY: 690240

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49314

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078974

Other (OTH) AF: 0.00 AC: 0 AN: 58022

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		8.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.58	P
Vest4		0.44
MutPred		0.50		Gain of loop (P = 0.1069)
MVP		0.47
ClinPred		0.86	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.58
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs2034059727; hg19: chr11-8641616;