rs144335584

Variant names:

• chr4-39232258-A-G
• rs144335584
• NM_025132.4:c.2239A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_025132.4(WDR19):​c.2239A>G​(p.Ile747Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,608,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.81
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P
• ciliopathy

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005393535).
• BP6: Variant 4-39232258-A-G is Benign according to our data. Variant chr4-39232258-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476156.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000454 (69/152062) while in subpopulation EAS AF = 0.00776 (40/5156). AF 95% confidence interval is 0.00586. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2239A>G	p.Ile747Val	missense	Exon 19 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.1759A>G	p.Ile587Val	missense	Exon 18 of 36	NP_001304853.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR19	ENST00000399820.8	TSL:1 MANE Select	c.2239A>G	p.Ile747Val	missense	Exon 19 of 37	ENSP00000382717.3
	WDR19	ENST00000959578.1		c.2239A>G	p.Ile747Val	missense	Exon 19 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.2173A>G	p.Ile725Val	missense	Exon 18 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.000461 AC: 70 AN: 151946 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00793

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000766 AC: 186 AN: 242894 AF XY: 0.000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00685

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000679

GnomAD4 exome AF: 0.000367 AC: 534 AN: 1456002 Hom.: 1 Cov.: 31 AF XY: 0.000398 AC XY: 288 AN XY: 724028

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 43544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00888 AC: 352 AN: 39658

South Asian (SAS) AF: 0.000719 AC: 61 AN: 84808

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53312

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1109624

Other (OTH) AF: 0.000432 AC: 26 AN: 60186

GnomAD4 genome AF: 0.000454 AC: 69 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 39 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41488

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00776 AC: 40 AN: 5156

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67988

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000399 Hom.: 1

Bravo AF: 0.000506

ExAC AF: 0.000786 AC: 95

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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	Cranioectodermal dysplasia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.0090
DANN	Benign	0.80
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.26	N
PhyloP100		-1.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.17
Sift	Benign	0.45	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.24
MPC		0.14
ClinPred		0.0082	T
GERP RS		-3.1
Varity_R		0.027
gMVP		0.085
Mutation Taster		=97/3	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: rs144335584; hg19: chr4-39233878; COSMIC: COSV56465773; COSMIC: COSV56465773;