rs776659376

Variant names:

• chr4-39225033-A-G
• rs776659376
• NM_025132.4:c.1629A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_025132.4(WDR19):​c.1629A>G​(p.Pro543Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,396,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: WDR19 NM_025132.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00008235
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.13
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-39225033-A-G is Benign according to our data. Variant chr4-39225033-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261860.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR19	NM_025132.4	MANE Select	c.1629A>G	p.Pro543Pro	splice_region synonymous	Exon 15 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.1149A>G	p.Pro383Pro	splice_region synonymous	Exon 14 of 36	NP_001304853.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR19	ENST00000399820.8	TSL:1 MANE Select	c.1629A>G	p.Pro543Pro	splice_region synonymous	Exon 15 of 37	ENSP00000382717.3
	WDR19	ENST00000959578.1		c.1629A>G	p.Pro543Pro	splice_region synonymous	Exon 15 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.1563A>G	p.Pro521Pro	splice_region synonymous	Exon 14 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000598 AC: 1 AN: 167106 AF XY: 0.0000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1396834 Hom.: 0 Cov.: 32 AF XY: 0.0000232 AC XY: 16 AN XY: 689274

African (AFR) AF: 0.00 AC: 0 AN: 31328

American (AMR) AF: 0.00 AC: 0 AN: 32490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 37838

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.0000259 AC: 28 AN: 1080714

Other (OTH) AF: 0.0000346 AC: 2 AN: 57874

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.8
DANN	Benign	0.68
PhyloP100		-1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.0		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: rs776659376; hg19: chr4-39226653;