4-176125308-A-G

Position:

• chr4-176125308-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181265.4(WDR17):​c.743A>G​(p.Gln248Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: WDR17 NM_181265.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

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

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=0.3204474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR17	NM_181265.4	c.743A>G	p.Gln248Arg	missense_variant	5/29	ENST00000508596.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR17	ENST00000508596.6	c.743A>G	p.Gln248Arg	missense_variant	5/29	1	NM_181265.4	P1
WDR17	ENST00000280190.8	c.815A>G	p.Gln272Arg	missense_variant	6/31	1
WDR17	ENST00000507824.6	c.764A>G	p.Gln255Arg	missense_variant	5/30	5
WDR17	ENST00000505894.2	c.231+5211A>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

EpiCase AF: 0.0000547

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2023

The c.815A>G (p.Q272R) alteration is located in exon 6 (coding exon 5) of the WDR17 gene. This alteration results from a A to G substitution at nucleotide position 815, causing the glutamine (Q) at amino acid position 272 to be replaced by an arginine (R). 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	0.085
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.0062	.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.29
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.0090	.;B;.
Vest4		0.38
MVP		0.76
MPC		0.53
ClinPred		0.67	D
GERP RS		4.1
Varity_R		0.18
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1579115988; hg19: chr4-177046459;