Genetic Variant RNF126:p.Pro283Ala (chr19-648217-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_194460.3(RNF126):c.847C>G(p.Pro283Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,450,252 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: 0.0000034 ( 0 hom. )

Consequence

RNF126
NM_194460.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3207966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3 link	c.847C>G	p.Pro283Ala	missense_variant	Exon 9 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.766C>G	p.Pro256Ala	missense_variant	Exon 9 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.*271C>G		downstream_gene_variant			XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10 link	c.847C>G	p.Pro283Ala	missense_variant	Exon 9 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000442

AC:

AN:

226028

AF XY:

0.00000818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000531

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1450252

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

720264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33290

American (AMR)

AF:

0.00

AC:

AN:

43122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39112

South Asian (SAS)

AF:

0.00

AC:

AN:

84292

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1106794

Other (OTH)

AF:

0.00

AC:

AN:

59888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.847C>G (p.P283A) alteration is located in exon 9 (coding exon 9) of the RNF126 gene. This alteration results from a C to G substitution at nucleotide position 847, causing the proline (P) at amino acid position 283 to be replaced by an alanine (A). 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

0.085

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

PhyloP100

7.8

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.9

D;.

REVEL

Benign

0.18

Sift

Benign

0.14

T;.

Sift4G

Benign

0.26

T;.

Vest4

0.44

MutPred

0.17

Loss of glycosylation at P283 (P = 0.03);.;

MVP

0.22

MPC

0.72

ClinPred

0.85

GERP RS

3.8

Varity_R

0.26

Mutation Taster

=56/44

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

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19-648217-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over