4-183650986-C-T

Variant names:

• chr4-183650986-C-T
• rs140946722
• NM_152682.4:c.361G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_152682.4(RWDD4):​c.361G>A​(p.Ala121Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000079 in 1,608,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: RWDD4 NM_152682.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003933
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.131

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010046005).
• BP6: Variant 4-183650986-C-T is Benign according to our data. Variant chr4-183650986-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3791557.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RWDD4	NM_152682.4	c.361G>A	p.Ala121Thr	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000326397.10	NP_689895.2
RWDD4	XM_047449748.1	c.361G>A	p.Ala121Thr	missense_variant	Exon 4 of 5		XP_047305704.1
RWDD4	NM_001307922.2	c.172G>A	p.Ala58Thr	missense_variant, splice_region_variant	Exon 4 of 8		NP_001294851.1
RWDD4	XM_047449747.1	c.337G>A	p.Ala113Thr	missense_variant, splice_region_variant	Exon 4 of 8		XP_047305703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RWDD4	ENST00000326397.10	c.361G>A	p.Ala121Thr	missense_variant, splice_region_variant	Exon 4 of 8	2	NM_152682.4	ENSP00000388920.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000133 AC: 33 AN: 248766 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 134234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000270

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000797 AC: 116 AN: 1455868 Hom.: 0 Cov.: 31 AF XY: 0.0000898 AC XY: 65 AN XY: 723554

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000478

Gnomad4 OTH exome AF: 0.0000999

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74418

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 04, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.77
DEOGEN2	Benign	0.0021	T;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.045	N;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.070	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.076
MVP		0.38
MPC		0.27
ClinPred		0.012	T
GERP RS		-8.6
Varity_R		0.024
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.068
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: rs140946722; hg19: chr4-184572139;