Genetic Variant NM_015485.5:c.258T>G (chr1-95244383-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_015485.5(RWDD3):c.258T>G(p.Asn86Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,613,960 control chromosomes in the GnomAD database, including 603,401 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 0.82 ( 51859 hom., cov: 32)

Exomes 𝑓: 0.87 ( 551542 hom. )

Consequence

RWDD3
NM_015485.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.117

Publications

40 publications found

Variant links:

Genes affected

RWDD3 (HGNC:21393): (RWD domain containing 3) Involved in negative regulation of NF-kappaB transcription factor activity; positive regulation of hypoxia-inducible factor-1alpha signaling pathway; and positive regulation of protein sumoylation. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RWDD3 links:

TLCD4-RWDD3 (HGNC:49388): (TLCD4-RWDD3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring TMEM56 (transmembrane protein 56) and RWDD3 (RWD domain containing 3) genes on chromosome 1. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product, but it contains a distinct C-terminus due to frameshifts versus the downstream gene coding sequence. [provided by RefSeq, Dec 2010]

TLCD4-RWDD3 links:

ENSG00000228852 (HGNC:):

ENSG00000228852 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=2.5616014E-6).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RWDD3	NM_015485.5 link	c.258T>G	p.Asn86Lys	missense_variant	Exon 2 of 4	ENST00000370202.5	NP_056300.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RWDD3	ENST00000370202.5 link	c.258T>G	p.Asn86Lys	missense_variant	Exon 2 of 4	3	NM_015485.5	ENSP00000359221.4		Q9Y3V2-1
TLCD4-RWDD3	ENST00000604534.5 link	c.*133T>G		3_prime_UTR_variant	Exon 8 of 8	2		ENSP00000475025.1		S4R434

Frequencies

GnomAD3 genomes

AF:

0.822

AC:

124990

AN:

151984

Hom.:

51836

Cov.:

show subpopulations

Gnomad AFR

AF:

0.717

Gnomad AMI

AF:

0.829

Gnomad AMR

AF:

0.823

Gnomad ASJ

AF:

0.876

Gnomad EAS

AF:

0.782

Gnomad SAS

AF:

0.936

Gnomad FIN

AF:

0.883

Gnomad MID

AF:

0.905

Gnomad NFE

AF:

0.868

Gnomad OTH

AF:

0.842

GnomAD2 exomes

AF:

0.855

AC:

213310

AN:

249484

AF XY:

0.862

show subpopulations

Gnomad AFR exome

AF:

0.707

Gnomad AMR exome

AF:

0.827

Gnomad ASJ exome

AF:

0.872

Gnomad EAS exome

AF:

0.775

Gnomad FIN exome

AF:

0.876

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.868

GnomAD4 exome

AF:

0.868

AC:

1268515

AN:

1461858

Hom.:

551542

Cov.:

AF XY:

0.871

AC XY:

633206

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.709

AC:

23723

AN:

33480

American (AMR)

AF:

0.824

AC:

36850

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.870

AC:

22740

AN:

26136

East Asian (EAS)

AF:

0.803

AC:

31883

AN:

39698

South Asian (SAS)

AF:

0.944

AC:

81469

AN:

86258

European-Finnish (FIN)

AF:

0.872

AC:

46595

AN:

53414

Middle Eastern (MID)

AF:

0.901

AC:

5197

AN:

5768

European-Non Finnish (NFE)

AF:

0.871

AC:

968029

AN:

1111986

Other (OTH)

AF:

0.861

AC:

52029

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

10432

20864

31296

41728

52160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21266

42532

63798

85064

106330

<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:

0.822

AC:

125063

AN:

152102

Hom.:

51859

Cov.:

AF XY:

0.824

AC XY:

61277

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.716

AC:

29701

AN:

41456

American (AMR)

AF:

0.823

AC:

12576

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.876

AC:

3042

AN:

3472

East Asian (EAS)

AF:

0.781

AC:

4018

AN:

5146

South Asian (SAS)

AF:

0.936

AC:

4511

AN:

4822

European-Finnish (FIN)

AF:

0.883

AC:

9355

AN:

10600

Middle Eastern (MID)

AF:

0.905

AC:

266

AN:

294

European-Non Finnish (NFE)

AF:

0.868

AC:

59054

AN:

68008

Other (OTH)

AF:

0.845

AC:

1784

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1116

2233

3349

4466

5582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.852

Hom.:

184576

Bravo

AF:

0.811

TwinsUK

AF:

0.872

AC:

3232

ALSPAC

AF:

0.872

AC:

3362

ESP6500AA

AF:

0.722

AC:

2790

ESP6500EA

AF:

0.866

AC:

7172

ExAC

AF:

0.855

AC:

103244

Asia WGS

AF:

0.869

AC:

3022

AN:

3478

EpiCase

AF:

0.869

EpiControl

AF:

0.869

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.1

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0013

T;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.040

T;T

MetaRNN

Benign

0.0000026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.6

N;N

PhyloP100

-0.12

PrimateAI

Benign

0.36

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.036

MutPred

0.42

Gain of ubiquitination at N86 (P = 0.0138);Gain of ubiquitination at N86 (P = 0.0138);

MPC

0.13

ClinPred

0.0051

GERP RS

-1.5

Varity_R

0.034

gMVP

0.17

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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