Genetic Variant RNF126:p.Val218Ile (chr19-648900-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_194460.3(RNF126):c.652G>A(p.Val218Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,427,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

RNF126
NM_194460.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95

Publications

1 publications found

Variant links:

Genes affected

RNF126 (HGNC:21151): (ring finger protein 126) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. [provided by RefSeq, Jul 2008]

RNF126 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047290415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3 link	c.652G>A	p.Val218Ile	missense_variant	Exon 7 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.571G>A	p.Val191Ile	missense_variant	Exon 7 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.729G>A	p.Pro243Pro	synonymous_variant	Exon 7 of 8		XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10 link	c.652G>A	p.Val218Ile	missense_variant	Exon 7 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000594

AC:

AN:

134644

AF XY:

0.0000689

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000151

Gnomad ASJ exome

AF:

0.000445

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000565

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000408

AC:

AN:

1275718

Hom.:

Cov.:

AF XY:

0.0000516

AC XY:

AN XY:

620480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26986

American (AMR)

AF:

0.0000458

AC:

AN:

21814

Ashkenazi Jewish (ASJ)

AF:

0.000112

AC:

AN:

17824

East Asian (EAS)

AF:

0.00

AC:

AN:

33502

South Asian (SAS)

AF:

0.0000380

AC:

AN:

52586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3986

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

1021040

Other (OTH)

AF:

0.0000193

AC:

AN:

51858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000590

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.652G>A (p.V218I) alteration is located in exon 7 (coding exon 7) of the RNF126 gene. This alteration results from a G to A substitution at nucleotide position 652, causing the valine (V) at amino acid position 218 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

0.086

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.023

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.73

N;.

PhyloP100

2.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.040

N;.

REVEL

Benign

0.095

Sift

Benign

0.99

T;.

Sift4G

Benign

1.0

T;.

Vest4

0.23

MutPred

0.41

Loss of disorder (P = 0.1146);.;

MVP

0.17

MPC

0.17

ClinPred

0.056

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

Mutation Taster

=85/15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr19-648900-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over