4-183649555-T-C

Variant names:

• chr4-183649555-T-C
• rs756143023
• NM_152682.4:c.377A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152682.4(RWDD4):​c.377A>G​(p.Asn126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000383 in 1,565,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: RWDD4 NM_152682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05644068).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152682.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RWDD4	NM_152682.4	MANE Select	c.377A>G	p.Asn126Ser	missense	Exon 5 of 8	NP_689895.2	Q6NW29-1
	RWDD4	NM_001307922.2		c.188A>G	p.Asn63Ser	missense	Exon 5 of 8	NP_001294851.1	E7EV43

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RWDD4	ENST00000326397.10	TSL:2 MANE Select	c.377A>G	p.Asn126Ser	missense	Exon 5 of 8	ENSP00000388920.2	Q6NW29-1
	RWDD4	ENST00000327570.13	TSL:3	c.377A>G	p.Asn126Ser	missense	Exon 5 of 7	ENSP00000332177.9	K4DI92
	RWDD4	ENST00000512740.1	TSL:5	c.188A>G	p.Asn63Ser	missense	Exon 4 of 7	ENSP00000423598.1	E7EV43

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149954 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000251

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000217 AC: 5 AN: 229996 AF XY: 0.0000160

Gnomad AFR exome AF: 0.000339

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1415552 Hom.: 0 Cov.: 25 AF XY: 0.00000283 AC XY: 2 AN XY: 706144

African (AFR) AF: 0.000157 AC: 5 AN: 31790

American (AMR) AF: 0.00 AC: 0 AN: 41426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25498

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 82476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077368

Other (OTH) AF: 0.00 AC: 0 AN: 58708

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149954 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73190

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000251 AC: 1 AN: 39812

American (AMR) AF: 0.00 AC: 0 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67842

Other (OTH) AF: 0.00 AC: 0 AN: 2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.76
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		1.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.075
Sift	Benign	0.61	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.33		Gain of sheet (P = 0.0344)
MVP		0.40
MPC		0.22
ClinPred		0.0057	T
GERP RS		2.6
Varity_R		0.035
gMVP		0.078
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756143023; hg19: chr4-184570708;