chr4-176125238-C-T

Variant names:

• chr4-176125238-C-T
• rs770285329
• NM_181265.4:c.673C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181265.4(WDR17):​c.673C>T​(p.Arg225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: WDR17 NM_181265.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30
• Publications: 5 publications found

Genes affected

WDR17 (HGNC:16661): (WD repeat domain 17) This gene encodes a WD repeat-containing protein. It is abundantly expressed in retina and testis, and is thought to be a candidate gene for retinal disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181265.4. 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
	WDR17	NM_181265.4	MANE Select	c.673C>T	p.Arg225Cys	missense	Exon 5 of 29	NP_851782.3	Q8IZU2-2
	WDR17	NM_170710.5		c.745C>T	p.Arg249Cys	missense	Exon 6 of 31	NP_733828.2
	WDR17	NM_001350727.2		c.673C>T	p.Arg225Cys	missense	Exon 5 of 31	NP_001337656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR17	ENST00000508596.6	TSL:1 MANE Select	c.673C>T	p.Arg225Cys	missense	Exon 5 of 29	ENSP00000422763.1	Q8IZU2-2
	WDR17	ENST00000280190.8	TSL:1	c.745C>T	p.Arg249Cys	missense	Exon 6 of 31	ENSP00000280190.4	Q8IZU2-1
	WDR17	ENST00000507824.6	TSL:5	c.694C>T	p.Arg232Cys	missense	Exon 5 of 30	ENSP00000422200.2	E7ESC9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251402 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727232

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111996

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	0.18
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.67		Gain of catalytic residue at L250 (P = 0.0107)
MVP		0.82
MPC		0.60
ClinPred		0.24	T
GERP RS		4.9
Varity_R		0.26
gMVP		0.72
Mutation Taster		=85/15	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: rs770285329; hg19: chr4-177046389; COSMIC: COSV54568804; COSMIC: COSV54568804;