NM_015485.5:c.26T>G

Variant names:

• chr1-95234256-T-G
• NM_015485.5:c.26T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015485.5(RWDD3):​c.26T>G​(p.Leu9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000485 in 1,444,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RWDD3 NM_015485.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37
• 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]

RWDD3-DT (HGNC:55839): (RWDD3 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

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.26T>G	p.Leu9Arg	missense	Exon 1 of 4	NP_056300.3	Q9Y3V2-1
	RWDD3	NM_001199682.2		c.26T>G	p.Leu9Arg	missense	Exon 1 of 4	NP_001186611.2	Q9Y3V2-4
	RWDD3	NM_001128142.2		c.26T>G	p.Leu9Arg	missense	Exon 1 of 3	NP_001121614.2	Q9Y3V2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RWDD3	ENST00000370202.5	TSL:3 MANE Select	c.26T>G	p.Leu9Arg	missense	Exon 1 of 4	ENSP00000359221.4	Q9Y3V2-1
	RWDD3	ENST00000263893.10	TSL:1	c.26T>G	p.Leu9Arg	missense	Exon 1 of 3	ENSP00000263893.6	Q9Y3V2-2
	TLCD4-RWDD3	ENST00000604534.5	TSL:2	c.566+3262T>G		intron	N/A	ENSP00000475025.1	S4R434

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1444740 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 716854

African (AFR) AF: 0.00 AC: 0 AN: 33230

American (AMR) AF: 0.00 AC: 0 AN: 42722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 39012

South Asian (SAS) AF: 0.00 AC: 0 AN: 83168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1104342

Other (OTH) AF: 0.00 AC: 0 AN: 59680

GnomAD4 genome Cov.: 33

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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.91	P
Vest4		0.92
MutPred		0.81		Gain of disorder (P = 0.0374)
MVP		0.54
MPC		0.64
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.90
gMVP		0.86
Mutation Taster		=48/52	disease causing

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

hg19: chr1-95699812;