4-176115805-C-A

Variant names:

• chr4-176115805-C-A
• rs201837131
• NM_181265.4:c.133C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181265.4(WDR17):​c.133C>A​(p.Arg45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WDR17 NM_181265.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29066283).

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.133C>A	p.Arg45Ser	missense	Exon 3 of 29	NP_851782.3	Q8IZU2-2
	WDR17	NM_170710.5		c.205C>A	p.Arg69Ser	missense	Exon 4 of 31	NP_733828.2
	WDR17	NM_001350727.2		c.133C>A	p.Arg45Ser	missense	Exon 3 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.133C>A	p.Arg45Ser	missense	Exon 3 of 29	ENSP00000422763.1	Q8IZU2-2
	WDR17	ENST00000280190.8	TSL:1	c.205C>A	p.Arg69Ser	missense	Exon 4 of 31	ENSP00000280190.4	Q8IZU2-1
	WDR17	ENST00000507824.6	TSL:5	c.205C>A	p.Arg69Ser	missense	Exon 3 of 30	ENSP00000422200.2	E7ESC9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445160 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718340

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

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 43224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 38900

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104120

Other (OTH) AF: 0.00 AC: 0 AN: 59604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.053
Sift	Benign	0.16	T
Sift4G	Benign	0.48	T
Polyphen		0.44	B
Vest4		0.41
MutPred		0.47		Loss of ubiquitination at K74 (P = 0.0755)
MVP		0.82
MPC		0.15
ClinPred		0.48	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.19
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201837131; hg19: chr4-177036956;