rs201354264

Variant names:

• chr4-39255854-A-G
• rs201354264
• NM_025132.4:c.3008A>G
• WDR19 p.Glu1003Gly

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025132.4(WDR19):​c.3008A>G​(p.Glu1003Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000959 in 1,583,332 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1003K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (10 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 4.46
• Publications: 2 publications found

Genes affected

WDR19 (HGNC:18340): (WD repeat domain 19) The protein encoded by this gene is a member of the WD (tryptophan-aspartic acid) repeat family, which is a large family of structurally-related proteins known to participate in a wide range of cellular processes. Each WD repeat typically contains about 40 amino acids that are usually bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. This protein contains six WD repeats, three transmembrane domains, and a clathrin heavy-chain repeat. Mutations in this gene have been described in individuals with a wide range of disorders affecting function of the cilium. These disorders are known as ciliopathies, and include Jeune syndrome, Sensenbrenner syndromes, Senior-Loken syndrome, combined or isolated nephronophthisis (NPHP), and retinitis pigmentosa (RP). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

WDR19 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cranioectodermal dysplasia 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• nephronophthisis 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009061396).
• BP6: Variant 4-39255854-A-G is Benign according to our data. Variant chr4-39255854-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437272.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00065 (99/152306) while in subpopulation SAS AF = 0.0029 (14/4824). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025132.4. 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
	WDR19	NM_025132.4	MANE Select	c.3008A>G	p.Glu1003Gly	missense	Exon 27 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.2528A>G	p.Glu843Gly	missense	Exon 26 of 36	NP_001304853.1	B4DGR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR19	ENST00000399820.8	TSL:1 MANE Select	c.3008A>G	p.Glu1003Gly	missense	Exon 27 of 37	ENSP00000382717.3	Q8NEZ3-1
	WDR19	ENST00000959578.1		c.3020A>G	p.Glu1007Gly	missense	Exon 27 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.2942A>G	p.Glu981Gly	missense	Exon 26 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00117 AC: 260 AN: 222972 AF XY: 0.00143

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000566

Gnomad ASJ exome AF: 0.000965

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000992 AC: 1419 AN: 1431026 Hom.: 10 Cov.: 29 AF XY: 0.00110 AC XY: 783 AN XY: 709092

African (AFR) AF: 0.000152 AC: 5 AN: 32816

American (AMR) AF: 0.000609 AC: 25 AN: 41038

Ashkenazi Jewish (ASJ) AF: 0.000830 AC: 21 AN: 25312

East Asian (EAS) AF: 0.00 AC: 0 AN: 39120

South Asian (SAS) AF: 0.00331 AC: 264 AN: 79794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52514

Middle Eastern (MID) AF: 0.00721 AC: 41 AN: 5684

European-Non Finnish (NFE) AF: 0.000896 AC: 981 AN: 1095474

Other (OTH) AF: 0.00138 AC: 82 AN: 59274

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74484

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.000691

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Asphyxiating thoracic dystrophy 5 (1)
-	-	1	Asphyxiating thoracic dystrophy 5;C3280612:Nephronophthisis 13;C3280616:Cranioectodermal dysplasia 4;C4225376:Senior-Loken syndrome 8;C5676980:Spermatogenic failure 72 (1)
-	-	1	Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 (1)
-	1	-	Connective tissue disorder (1)
-	-	1	Cranioectodermal dysplasia 4 (1)
-	1	-	not specified (1)
-	-	1	WDR19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.11
Sift	Benign	0.078	T
Sift4G	Benign	0.13	T
Varity_R		0.075
gMVP		0.30
Mutation Taster		=84/16	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201354264;

hg19: chr4-39257474;

COSMIC: COSV107310698;