Genetic Variant NM_025236.4:c.707C>A (chr6-30071463-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_025236.4(RNF39):c.707C>A(p.Ala236Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,556,918 control chromosomes in the GnomAD database, including 15,551 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2738 hom., cov: 33)

Exomes 𝑓: 0.12 ( 12813 hom. )

Consequence

RNF39
NM_025236.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

Publications

41 publications found

Variant links:

Genes affected

RNF39 (HGNC:18064): (ring finger protein 39) This gene lies within the major histocompatibility complex class I region on chromosome 6. Studies of a similar rat protein suggest that this gene encodes a protein that plays a role in an early phase of synaptic plasticity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RNF39 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032743216).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF39	NM_025236.4 link	c.707C>A	p.Ala236Glu	missense_variant	Exon 4 of 4	ENST00000244360.8	NP_079512.3	Q9H2S5Q96QB5
RNF39	NM_170769.3 link	c.707C>A	p.Ala236Glu	missense_variant	Exon 4 of 5		NP_739575.3	Q9H2S5A0A1U9X8G2
RNF39	XM_017011325.2 link	c.452C>A	p.Ala151Glu	missense_variant	Exon 3 of 3		XP_016866814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF39	ENST00000244360.8 link	c.707C>A	p.Ala236Glu	missense_variant	Exon 4 of 4	1	NM_025236.4	ENSP00000244360.7		Q9H2S5
RNF39	ENST00000376751.8 link	c.707C>A	p.Ala236Glu	missense_variant	Exon 4 of 5	1		ENSP00000365942.4		Q9H2S5

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25905

AN:

152094

Hom.:

2721

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.303

Gnomad EAS

AF:

0.189

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.0476

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.193

GnomAD2 exomes

AF:

0.176

AC:

28845

AN:

164144

AF XY:

0.170

show subpopulations

Gnomad AFR exome

AF:

0.309

Gnomad AMR exome

AF:

0.249

Gnomad ASJ exome

AF:

0.323

Gnomad EAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.0540

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.174

GnomAD4 exome

AF:

0.122

AC:

171319

AN:

1404706

Hom.:

12813

Cov.:

AF XY:

0.124

AC XY:

86135

AN XY:

697348

show subpopulations

African (AFR)

AF:

0.284

AC:

8616

AN:

30298

American (AMR)

AF:

0.238

AC:

8926

AN:

37482

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

7278

AN:

24260

East Asian (EAS)

AF:

0.260

AC:

9417

AN:

36278

South Asian (SAS)

AF:

0.171

AC:

13760

AN:

80456

European-Finnish (FIN)

AF:

0.0514

AC:

2096

AN:

40746

Middle Eastern (MID)

AF:

0.168

AC:

948

AN:

5628

European-Non Finnish (NFE)

AF:

0.102

AC:

111450

AN:

1091442

Other (OTH)

AF:

0.152

AC:

8828

AN:

58116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

8166

16331

24497

32662

40828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4260

8520

12780

17040

21300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.171

AC:

25957

AN:

152212

Hom.:

2738

Cov.:

AF XY:

0.168

AC XY:

12533

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.274

AC:

11394

AN:

41536

American (AMR)

AF:

0.211

AC:

3219

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1051

AN:

3472

East Asian (EAS)

AF:

0.189

AC:

971

AN:

5142

South Asian (SAS)

AF:

0.183

AC:

882

AN:

4826

European-Finnish (FIN)

AF:

0.0476

AC:

505

AN:

10610

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7445

AN:

68016

Other (OTH)

AF:

0.192

AC:

406

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1076

2152

3229

4305

5381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.141

Hom.:

2989

Bravo

AF:

0.191

TwinsUK

AF:

0.0982

AC:

364

ALSPAC

AF:

0.0854

AC:

329

ESP6500AA

AF:

0.251

AC:

753

ESP6500EA

AF:

0.118

AC:

637

ExAC

AF:

0.143

AC:

16432

Asia WGS

AF:

0.211

AC:

733

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.00036

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0069

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

N;N

PhyloP100

1.5

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.54

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.054

MPC

1.3

ClinPred

0.012

GERP RS

4.5

Varity_R

0.051

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over