11-4385818-A-G

Variant names:

• chr11-4385818-A-G
• NM_003141.4:c.895T>C

Variant summary

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

The NM_003141.4(TRIM21):​c.895T>C​(p.Trp299Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIM21 NM_003141.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.591
• Publications: 0 publications found

Genes affected

TRIM21 (HGNC:11312): (tripartite motif containing 21) This gene encodes 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 encoded protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

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=0.3221522).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003141.4. 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
	TRIM21	NM_003141.4	MANE Select	c.895T>C	p.Trp299Arg	missense	Exon 7 of 7	NP_003132.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM21	ENST00000254436.8	TSL:1 MANE Select	c.895T>C	p.Trp299Arg	missense	Exon 7 of 7	ENSP00000254436.7	P19474-1
	TRIM21	ENST00000934674.1		c.895T>C	p.Trp299Arg	missense	Exon 8 of 8	ENSP00000604733.1
	TRIM21	ENST00000962553.1		c.895T>C	p.Trp299Arg	missense	Exon 8 of 8	ENSP00000632612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460694 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726490

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111450

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

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	0.77
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.59
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.11
Sift	Benign	0.093	T
Sift4G	Benign	0.42	T
Polyphen		0.59	P
Vest4		0.38
MutPred		0.53		Gain of disorder (P = 0.003)
MVP		0.31
MPC		0.13
ClinPred		0.091	T
GERP RS		1.9
PromoterAI		0.0028	Neutral
Varity_R		0.15
gMVP		0.32
Mutation Taster		=90/10	polymorphism

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

hg19: chr11-4407048;