1-95234256-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RWDD3	NM_015485.5	c.26T>G	p.Leu9Arg	missense_variant	Exon 1 of 4	ENST00000370202.5	NP_056300.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RWDD3	ENST00000370202.5	c.26T>G	p.Leu9Arg	missense_variant	Exon 1 of 4	3	NM_015485.5	ENSP00000359221.4
TLCD4-RWDD3	ENST00000604534.5	c.566+3262T>G		intron_variant	Intron 7 of 7	2		ENSP00000475025.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000634

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26T>G (p.L9R) alteration is located in exon 1 (coding exon 1) of the RWDD3 gene. This alteration results from a T to G substitution at nucleotide position 26, causing the leucine (L) at amino acid position 9 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.91	P;D
Vest4		0.92
MutPred		0.81		Gain of disorder (P = 0.0374);Gain of disorder (P = 0.0374);
MVP		0.54
MPC		0.64
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.90
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-95699812;