dbSNP rs867036510: RNF126:p.Gly224Val (chr19-648487-C-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.671G>T(p.Gly224Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G224D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RNF126
NM_194460.3 missense, splice_region

Scores

Splicing: ADA: 0.9388

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.36

Publications

0 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:

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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.671G>T	p.Gly224Val	missense_variant, splice_region_variant	Exon 8 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.590G>T	p.Gly197Val	missense_variant, splice_region_variant	Exon 8 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.*1G>T		splice_region_variant	Exon 8 of 8		XP_047295025.1
RNF126	XM_047439069.1 link	c.*1G>T		3_prime_UTR_variant	Exon 8 of 8		XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10 link	c.671G>T	p.Gly224Val	missense_variant, splice_region_variant	Exon 8 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700758

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32028

American (AMR)

AF:

0.00

AC:

AN:

39474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25502

East Asian (EAS)

AF:

0.00

AC:

AN:

36650

South Asian (SAS)

AF:

0.00

AC:

AN:

80604

European-Finnish (FIN)

AF:

0.0000221

AC:

AN:

45230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4154

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092470

Other (OTH)

AF:

0.00

AC:

AN:

58652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000358

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.028

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

2.4

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.3

D;.

REVEL

Benign

0.17

Sift

Uncertain

0.015

D;.

Sift4G

Uncertain

0.036

D;.

Vest4

0.40

MutPred

0.41

Loss of disorder (P = 0.0568);.;

MVP

0.40

MPC

0.31

ClinPred

0.93

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over