rs259358

Variant names:

• chr1-95244265-T-C
• rs259358
• NM_015485.5:c.140T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015485.5(RWDD3):​c.140T>C​(p.Val47Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,614,210 control chromosomes in the GnomAD database, including 802,549 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 0.99 (74092 hom., cov: 33)
  • Exomes 𝑓: 1.0 (728457 hom.)
• Consequence: RWDD3 NM_015485.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 28 publications found

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]

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]

ENSG00000228852 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=8.6118024E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RWDD3	NM_015485.5	MANE Select	c.140T>C	p.Val47Ala	missense	Exon 2 of 4	NP_056300.3
	RWDD3	NM_001278248.2		c.95T>C	p.Val32Ala	missense	Exon 3 of 5	NP_001265177.2
	RWDD3	NM_001199682.2		c.140T>C	p.Val47Ala	missense	Exon 2 of 4	NP_001186611.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RWDD3	ENST00000370202.5	TSL:3 MANE Select	c.140T>C	p.Val47Ala	missense	Exon 2 of 4	ENSP00000359221.4
	RWDD3	ENST00000263893.10	TSL:1	c.140T>C	p.Val47Ala	missense	Exon 2 of 3	ENSP00000263893.6
	TLCD4-RWDD3	ENST00000604534.5	TSL:2	c.*15T>C		3_prime_UTR	Exon 8 of 8	ENSP00000475025.1

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150097 AN: 152204 Hom.: 74043 Cov.: 33

Gnomad AFR AF: 0.953

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.993

GnomAD2 exomes AF: 0.996 AC: 248567 AN: 249504 AF XY: 0.997

Gnomad AFR exome AF: 0.952

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.998 AC: 1459340 AN: 1461888 Hom.: 728457 Cov.: 75 AF XY: 0.999 AC XY: 726180 AN XY: 727246

African (AFR) AF: 0.946 AC: 31684 AN: 33480

American (AMR) AF: 0.997 AC: 44572 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26134 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86244 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53419 AN: 53420

Middle Eastern (MID) AF: 0.993 AC: 5727 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111703 AN: 1112006

Other (OTH) AF: 0.996 AC: 60157 AN: 60396

GnomAD4 genome AF: 0.986 AC: 150206 AN: 152322 Hom.: 74092 Cov.: 33 AF XY: 0.986 AC XY: 73446 AN XY: 74476

African (AFR) AF: 0.952 AC: 39588 AN: 41564

American (AMR) AF: 0.994 AC: 15200 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5174

South Asian (SAS) AF: 1.00 AC: 4831 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68021 AN: 68042

Other (OTH) AF: 0.993 AC: 2101 AN: 2116

Alfa AF: 0.995 Hom.: 188712

Bravo AF: 0.984

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.956 AC: 3598

ESP6500EA AF: 1.00 AC: 8230

ExAC AF: 0.996 AC: 120262

Asia WGS AF: 0.997 AC: 3468 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.12
DANN	Benign	0.43
DEOGEN2	Benign	0.0010	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.22	N
PhyloP100		-0.49
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.021
Sift	Benign	0.45	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.14
ClinPred		0.026	T
GERP RS		-9.2
Varity_R		0.015
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs259358; hg19: chr1-95709821; COSMIC: COSV107236013; COSMIC: COSV107236013;