19-58396619-C-T

Position:

• chr19-58396619-C-T

Variant summary

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

The NM_001195135.2(RNF225):​c.530C>T​(p.Pro177Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,826 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: 0.0000018 (0 hom.)
• Consequence: RNF225 NM_001195135.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.581

Genes affected

RNF225 (HGNC:51249): (ring finger protein 225) Predicted to enable metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.23592359).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF225	NM_001195135.2	c.530C>T	p.Pro177Leu	missense_variant	1/1	ENST00000601382.3	NP_001182064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF225	ENST00000601382.3	c.530C>T	p.Pro177Leu	missense_variant	1/1	6	NM_001195135.2	ENSP00000470441.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096826 Hom.: 0 Cov.: 31 AF XY: 0.00000190 AC XY: 1 AN XY: 525314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000326

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000232

GnomAD4 genome Cov.: 33

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 09, 2024

The c.530C>T (p.P177L) alteration is located in exon 1 (coding exon 1) of the RNF225 gene. This alteration results from a C to T substitution at nucleotide position 530, causing the proline (P) at amino acid position 177 to be replaced by a leucine (L). 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	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.24	T
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.018	D
Vest4		0.20
MVP		0.89
GERP RS		3.3
Varity_R		0.076
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs1599937118; hg19: chr19-58907986;