1-95246544-G-C

Variant names:

• chr1-95246544-G-C
• rs758665085
• NM_015485.5:c.576G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015485.5(RWDD3):​c.576G>C​(p.Glu192Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,402,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RWDD3 NM_015485.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.489
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17789707).

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.576G>C	p.Glu192Asp	missense splice_region	Exon 3 of 4	NP_056300.3	Q9Y3V2-1
	RWDD3	NM_001278248.2		c.531G>C	p.Glu177Asp	missense splice_region	Exon 4 of 5	NP_001265177.2
	RWDD3	NM_001199682.2		c.529G>C	p.Val177Leu	missense splice_region	Exon 3 of 4	NP_001186611.2	Q9Y3V2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RWDD3	ENST00000370202.5	TSL:3 MANE Select	c.576G>C	p.Glu192Asp	missense splice_region	Exon 3 of 4	ENSP00000359221.4	Q9Y3V2-1
	RWDD3	ENST00000263893.10	TSL:1	c.*3-212G>C		intron	N/A	ENSP00000263893.6	Q9Y3V2-2
	RWDD3	ENST00000930354.1		c.693G>C	p.Glu231Asp	missense splice_region	Exon 3 of 4	ENSP00000600413.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1402892 Hom.: 0 Cov.: 24 AF XY: 0.00000142 AC XY: 1 AN XY: 701900

African (AFR) AF: 0.00 AC: 0 AN: 32002

American (AMR) AF: 0.00 AC: 0 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 39272

South Asian (SAS) AF: 0.00 AC: 0 AN: 84622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060788

Other (OTH) AF: 0.0000342 AC: 2 AN: 58404

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.49
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.060
Sift	Benign	0.21	T
Sift4G	Benign	0.24	T
Polyphen		0.45	B
Vest4		0.23
MutPred		0.51		Loss of ubiquitination at K191 (P = 0.0573)
MVP		0.59
MPC		0.14
ClinPred		0.96	D
GERP RS		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.41
Mutation Taster		=73/27	polymorphism

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: rs758665085; hg19: chr1-95712100;