Genetic Variant RNF19B:p.Met710Ile (chr1-32936872-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001300826.2(RNF19B):c.2130G>A(p.Met710Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RNF19B
NM_001300826.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

RNF19B (HGNC:26886): (ring finger protein 19B) This gene encodes a multi-pass membrane protein containing two RING-type and one IBR-type zinc finger motifs. The encoded protin is an E3 ubiquitin-protein ligase that plays a role in the cytotoxic effects of natural killer (NK) cells. Alternative splicing results in multiple transcript variants. There are pseudogenes for this gene on chromosomes X and Y in a possible pseudoautosomal region. [provided by RefSeq, Jul 2014]

RNF19B links:

ENSG00000287691 (HGNC:):

ENSG00000287691 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.037912935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF19B	NM_001300826.2 link	c.2130G>A	p.Met710Ile	missense_variant	Exon 9 of 9	ENST00000235150.5	NP_001287755.1	Q6ZMZ0-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RNF19B	ENST00000235150.5 link	c.2130G>A	p.Met710Ile	missense_variant	Exon 9 of 9	1	NM_001300826.2	ENSP00000235150.4	Q6ZMZ0-4
RNF19B	ENST00000373456.11 link	c.2133G>A	p.Met711Ile	missense_variant	Exon 9 of 9	1		ENSP00000362555.7	Q6ZMZ0-1
RNF19B	ENST00000356990 link	c.*416G>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000349482.5	Q6ZMZ0-2
ENSG00000287691	ENST00000661031.1 link	n.363+2518C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249352

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134638

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

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:

0.00000342

AC:

AN:

1460004

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2133G>A (p.M711I) alteration is located in exon 9 (coding exon 9) of the RNF19B gene. This alteration results from a G to A substitution at nucleotide position 2133, causing the methionine (M) at amino acid position 711 to be replaced by an isoleucine (I). 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

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.090

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.15

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.025

Sift

Benign

0.57

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.0

B;.

Vest4

0.043

MutPred

0.25

Loss of catalytic residue at M711 (P = 0.0269);.;

MVP

0.11

MPC

0.48

ClinPred

0.048

GERP RS

3.9

Varity_R

0.10

gMVP

0.072

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over