NM_018150.4:c.1469C>A

Variant names:

• chr1-44649684-C-A
• rs1160105904
• NM_018150.4:c.1469C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_018150.4(RNF220):​c.1469C>A​(p.Thr490Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNF220 NM_018150.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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]

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

LOC107984950 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37208426).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF220	NM_018150.4	MANE Select	c.1469C>A	p.Thr490Asn	missense	Exon 13 of 15	NP_060620.2
	RNF220	NM_001376486.1		c.1547C>A	p.Thr516Asn	missense	Exon 13 of 15	NP_001363415.1
	RNF220	NM_001376487.1		c.1547C>A	p.Thr516Asn	missense	Exon 13 of 15	NP_001363416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF220	ENST00000361799.7	TSL:1 MANE Select	c.1469C>A	p.Thr490Asn	missense	Exon 13 of 15	ENSP00000354872.2	Q5VTB9-1
	RNF220	ENST00000355387.6	TSL:1	c.1469C>A	p.Thr490Asn	missense	Exon 13 of 15	ENSP00000347548.2	Q5VTB9-1
	RNF220	ENST00000925767.1		c.1472C>A	p.Thr491Asn	missense	Exon 13 of 15	ENSP00000595826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.38
Sift	Benign	0.34	T
Sift4G	Benign	0.52	T
Polyphen		0.15	B
Vest4		0.88
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0999)
MVP		0.35
MPC		0.89
ClinPred		0.65	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.77
Mutation Taster		=57/43	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

dbSNP: rs1160105904; hg19: chr1-45115356;