chr4-183641459-T-G

Position:

• chr4-183641459-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152682.4(RWDD4):​c.544A>C​(p.Thr182Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: RWDD4 NM_152682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20148453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RWDD4	NM_152682.4	c.544A>C	p.Thr182Pro	missense_variant	8/8	ENST00000326397.10	NP_689895.2
RWDD4	NM_001307922.2	c.355A>C	p.Thr119Pro	missense_variant	8/8		NP_001294851.1
RWDD4	XM_047449747.1	c.520A>C	p.Thr174Pro	missense_variant	8/8		XP_047305703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RWDD4	ENST00000326397.10	c.544A>C	p.Thr182Pro	missense_variant	8/8	2	NM_152682.4	ENSP00000388920.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Jul 15, 2021

The c.544A>C (p.T182P) alteration is located in exon 8 (coding exon 8) of the RWDD4 gene. This alteration results from a A to C substitution at nucleotide position 544, causing the threonine (T) at amino acid position 182 to be replaced by a proline (P). 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	0.79
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.57	P;.;.;.
Vest4		0.27
MutPred		0.19		Gain of glycosylation at S184 (P = 0.0134);.;.;.;
MVP		0.64
MPC		0.46
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.73
gMVP		0.14

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: rs1453458124; hg19: chr4-184562612;