Genetic Variant RWDD4:p.Ala66Thr (chr4-183651237-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_152682.4(RWDD4):c.196G>A(p.Ala66Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,364 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

RWDD4
NM_152682.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.35

Variant links:

Genes affected

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

RWDD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35301474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RWDD4	NM_152682.4 link	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 8	ENST00000326397.10	NP_689895.2	Q6NW29-1
RWDD4	NM_001307922.2 link	c.7G>A	p.Ala3Thr	missense_variant	Exon 3 of 8		NP_001294851.1	Q6NW29E7EV43
RWDD4	XM_047449747.1 link	c.172G>A	p.Ala58Thr	missense_variant	Exon 3 of 8		XP_047305703.1
RWDD4	XM_047449748.1 link	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 5		XP_047305704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RWDD4	ENST00000326397.10 link	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 8	2	NM_152682.4	ENSP00000388920.2		Q6NW29-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251348

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1461320

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74248

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>A (p.A66T) alteration is located in exon 3 (coding exon 3) of the RWDD4 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the alanine (A) at amino acid position 66 to be replaced by a threonine (T). 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

Benign

0.20

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.0040

T;.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.38

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.78

T;T;T

Sift4G

Benign

0.90

T;T;T

Polyphen

0.98

D;.;.

Vest4

0.58

MutPred

0.48

Loss of catalytic residue at A66 (P = 0.201);Loss of catalytic residue at A66 (P = 0.201);.;

MVP

0.59

MPC

0.59

ClinPred

0.35

GERP RS

5.3

Varity_R

0.17

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over