chr19-58396462-G-T

Position:

• chr19-58396462-G-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.373G>T​(p.Ala125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,265,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RNF225 NM_001195135.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.963

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=0.069871515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF225	NM_001195135.2	c.373G>T	p.Ala125Ser	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.373G>T	p.Ala125Ser	missense_variant	1/1	6	NM_001195135.2	ENSP00000470441.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000496 AC: 2 AN: 40344 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 23932

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1265648 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 622462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Jul 31, 2024

The c.373G>T (p.A125S) alteration is located in exon 1 (coding exon 1) of the RNF225 gene. This alteration results from a G to T substitution at nucleotide position 373, causing the alanine (A) at amino acid position 125 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.070	T
PrimateAI	Pathogenic	0.89	D
Sift4G	Benign	0.39	T
Vest4		0.049
MVP		0.47
GERP RS		2.2
Varity_R		0.028
gMVP		0.19

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: rs1369486535; hg19: chr19-58907829;