Genetic Variant RNF126:p.Pro203Ser (chr19-648945-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194460.3(RNF126):c.607C>T(p.Pro203Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000782 in 1,279,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

RNF126
NM_194460.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3 link	c.607C>T	p.Pro203Ser	missense_variant	Exon 7 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.526C>T	p.Pro176Ser	missense_variant	Exon 7 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.684C>T	p.Pro228Pro	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.607C>T	p.Pro203Ser	missense_variant	Exon 7 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.82e-7

AC:

AN:

1279290

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

621654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27000

American (AMR)

AF:

0.00

AC:

AN:

21496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17960

East Asian (EAS)

AF:

0.00

AC:

AN:

33594

South Asian (SAS)

AF:

0.00

AC:

AN:

52670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3910

European-Non Finnish (NFE)

AF:

9.76e-7

AC:

AN:

1024126

Other (OTH)

AF:

0.00

AC:

AN:

51990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.607C>T (p.P203S) alteration is located in exon 7 (coding exon 7) of the RNF126 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the proline (P) at amino acid position 203 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

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

2.9

M;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.4

D;.

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0090

D;.

Vest4

0.63

MutPred

0.36

Loss of catalytic residue at P202 (P = 0.0103);.;

MVP

0.37

MPC

0.79

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

Mutation Taster

=18/82

disease causing

(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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19-648945-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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