4-183658933-T-C

Position:

• chr4-183658933-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152682.4(RWDD4):​c.20A>G​(p.Gln7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000033 in 1,120,280 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: 0.000033 (0 hom.)
• Consequence: RWDD4 NM_152682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

Genes affected

RWDD4 (HGNC:23750): (RWD domain containing 4)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RWDD4	NM_152682.4	c.20A>G	p.Gln7Arg	missense_variant	1/8	ENST00000326397.10	NP_689895.2
RWDD4	XM_047449748.1	c.20A>G	p.Gln7Arg	missense_variant	1/5		XP_047305704.1
RWDD4	NM_001307922.2	c.-166A>G		5_prime_UTR_variant	1/8		NP_001294851.1
RWDD4	XM_047449747.1	c.-18A>G		5_prime_UTR_variant	1/8		XP_047305703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RWDD4	ENST00000326397.10	c.20A>G	p.Gln7Arg	missense_variant	1/8	2	NM_152682.4	ENSP00000388920	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000330 AC: 37 AN: 1120280 Hom.: 0 Cov.: 30 AF XY: 0.0000225 AC XY: 12 AN XY: 533948

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: 0.0000393

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.20A>G (p.Q7R) alteration is located in exon 1 (coding exon 1) of the RWDD4 gene. This alteration results from a A to G substitution at nucleotide position 20, causing the glutamine (Q) at amino acid position 7 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.077	T;T
Polyphen		0.90	P;.
Vest4		0.74
MutPred		0.75		Gain of glycosylation at S2 (P = 0.0135);Gain of glycosylation at S2 (P = 0.0135);
MVP		0.68
MPC		0.31
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.84
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs943676722; hg19: chr4-184580086;