Genetic Variant RNF126:p.Asp253Asn (chr19-648401-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_194460.3(RNF126):c.757G>A(p.Asp253Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000812 in 1,573,248 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 12 hom. )

Consequence

RNF126
NM_194460.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.733

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004915625).

BP6

Variant 19-648401-C-T is Benign according to our data. Variant chr19-648401-C-T is described in ClinVar as [Benign]. Clinvar id is 716582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3 link	c.757G>A	p.Asp253Asn	missense_variant	Exon 8 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.676G>A	p.Asp226Asn	missense_variant	Exon 8 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.*87G>A		downstream_gene_variant			XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10 link	c.757G>A	p.Asp253Asn	missense_variant	Exon 8 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00562

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00303

AC:

567

AN:

187034

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.000281

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00531

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.000790

AC:

1123

AN:

1421114

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

494

AN XY:

704336

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

32344

American (AMR)

AF:

0.0143

AC:

582

AN:

40806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25562

East Asian (EAS)

AF:

0.0109

AC:

407

AN:

37224

South Asian (SAS)

AF:

0.000234

AC:

AN:

81280

European-Finnish (FIN)

AF:

0.000969

AC:

AN:

44394

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.0000264

AC:

AN:

1096546

Other (OTH)

AF:

0.000646

AC:

AN:

58850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152134

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41510

American (AMR)

AF:

0.00628

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00563

AC:

AN:

5148

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67966

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000617

Hom.:

Bravo

AF:

0.00163

ESP6500AA

AF:

0.000461

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00194

AC:

229

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.030

T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.84

T;D

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;.

PhyloP100

0.73

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.060

N;.

REVEL

Benign

0.086

Sift

Benign

0.53

T;.

Sift4G

Benign

0.69

T;.

Vest4

0.42

MVP

0.20

MPC

0.20

ClinPred

0.0094

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

Mutation Taster

=89/11

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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19-648401-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over