Genetic Variant RNF220:p.Thr490Ile (chr1-44649684-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_018150.4(RNF220):c.1469C>T(p.Thr490Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T490N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RNF220
NM_018150.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

Genes affected

RNF220 (HGNC:25552): (ring finger protein 220) Predicted to enable ubiquitin protein ligase activity. Involved in positive regulation of canonical Wnt signaling pathway. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

RNF220 links:

TMEM53 (HGNC:26186): (transmembrane protein 53) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TMEM53 Gene-Disease associations (from GenCC):

craniotubular dysplasia, Ikegawa type
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
skeletal dysplasia
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

TMEM53 links:

LOC107984950 (HGNC:):

LOC107984950 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.2243 (below the threshold of 3.09). Trascript score misZ: 2.8161 (below the threshold of 3.09). GenCC associations: The gene is linked to leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018150.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF220	NM_018150.4	MANE Select	c.1469C>T	p.Thr490Ile	missense	Exon 13 of 15	NP_060620.2
RNF220	NM_001376486.1		c.1547C>T	p.Thr516Ile	missense	Exon 13 of 15	NP_001363415.1
RNF220	NM_001376487.1		c.1547C>T	p.Thr516Ile	missense	Exon 13 of 15	NP_001363416.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF220	ENST00000361799.7	TSL:1 MANE Select	c.1469C>T	p.Thr490Ile	missense	Exon 13 of 15	ENSP00000354872.2	Q5VTB9-1
RNF220	ENST00000355387.6	TSL:1	c.1469C>T	p.Thr490Ile	missense	Exon 13 of 15	ENSP00000347548.2	Q5VTB9-1
RNF220	ENST00000925767.1		c.1472C>T	p.Thr491Ile	missense	Exon 13 of 15	ENSP00000595826.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251412

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.3

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.56

Sift

Benign

0.19

Sift4G

Benign

0.22

Polyphen

0.079

Vest4

0.89

MutPred

0.25

Loss of disorder (P = 0.0482)

MVP

0.45

MPC

1.7

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.71

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over