Genetic Variant RNF6:p.Ala542Asp (chr13-26214257-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005977.4(RNF6):c.1625C>A(p.Ala542Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,102 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 9 hom. )

Consequence

RNF6
NM_005977.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.608

Variant links:

Genes affected

RNF6 (HGNC:10069): (ring finger protein 6) The protein encoded by this gene contains a RING-H2 finger motif. Deletions and mutations in this gene were detected in esophageal squamous cell carcinoma (ESCC), suggesting that this protein may be a potential tumor suppressor. Studies of the mouse counterpart suggested a role of this protein in the transcription regulation that controls germinal differentiation. Multiple alternatively spliced transcript variants encoding the same protein are observed. [provided by RefSeq, Jul 2008]

RNF6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030345023).

BP6

Variant 13-26214257-G-T is Benign according to our data. Variant chr13-26214257-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 728784.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF6	NM_005977.4 link	c.1625C>A	p.Ala542Asp	missense_variant	Exon 5 of 5	ENST00000381588.9	NP_005968.1	Q9Y252-1A0A024RDP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RNF6	ENST00000381588.9 link	c.1625C>A	p.Ala542Asp	missense_variant	Exon 5 of 5	1	NM_005977.4	ENSP00000371000.4	Q9Y252-1
RNF6	ENST00000346166.7 link	c.1625C>A	p.Ala542Asp	missense_variant	Exon 5 of 5	1		ENSP00000342121.3	Q9Y252-1
RNF6	ENST00000381570.7 link	c.1625C>A	p.Ala542Asp	missense_variant	Exon 5 of 5	1		ENSP00000370982.3	Q9Y252-1
RNF6	ENST00000468480.5 link	n.768+1217C>A		intron_variant	Intron 5 of 5	1

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00195

AC:

491

AN:

251426

Hom.:

AF XY:

0.00191

AC XY:

259

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00332

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00504

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00208

AC:

3036

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1458

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00324

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00408

Gnomad4 NFE exome

AF:

0.00217

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00208

AC:

316

AN:

152212

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.00216

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00216

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00150

AC:

182

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00172

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 11, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

T;T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.41

.;.;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

L;L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.025

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.11

MVP

0.24

MPC

0.45

ClinPred

0.0016

GERP RS

0.80

Varity_R

0.098

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over