chr1-95244383-T-G

Variant names:

• chr1-95244383-T-G
• rs2296308
• NM_015485.5:c.258T>G

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 40 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=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	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	c.258T>G	p.Asn86Lys	missense_variant	Exon 2 of 4	3	NM_015485.5	ENSP00000359221.4
TLCD4-RWDD3	ENST00000604534.5	c.*133T>G		3_prime_UTR_variant	Exon 8 of 8	2		ENSP00000475025.1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124990 AN: 151984 Hom.: 51836 Cov.: 32

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

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.: 71 AF XY: 0.871 AC XY: 633206 AN XY: 727232

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

GnomAD4 genome AF: 0.822 AC: 125063 AN: 152102 Hom.: 51859 Cov.: 32 AF XY: 0.824 AC XY: 61277 AN XY: 74366

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

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	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.49
DEOGEN2	Benign	0.0013	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.040	T;T
MetaRNN	Benign	0.0000026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	N;N
PhyloP100		-0.12
PrimateAI	Benign	0.36	T
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	T
GERP RS		-1.5
Varity_R		0.034
gMVP		0.17
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2296308; hg19: chr1-95709939; COSMIC: COSV107236014; COSMIC: COSV107236014;