rs2167494

Variant names:

• chr4-39214601-C-T
• rs2167494
• NM_025132.4:c.891C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025132.4(WDR19):​c.891C>T​(p.Cys297Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,509,908 control chromosomes in the GnomAD database, including 66,124 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6791 hom., cov: 31)
  • Exomes 𝑓: 0.29 (59333 hom.)
• Consequence: WDR19 NM_025132.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005476
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.52
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-39214601-C-T is Benign according to our data. Variant chr4-39214601-C-T is described in ClinVar as Benign. ClinVar VariationId is 261867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

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.891C>T	p.Cys297Cys	splice_region synonymous	Exon 10 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.411C>T	p.Cys137Cys	splice_region synonymous	Exon 9 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.891C>T	p.Cys297Cys	splice_region synonymous	Exon 10 of 37	ENSP00000382717.3
	WDR19	ENST00000503697.5	TSL:1	n.*359C>T		splice_region non_coding_transcript_exon	Exon 8 of 9	ENSP00000423706.1
	WDR19	ENST00000503697.5	TSL:1	n.*359C>T		3_prime_UTR	Exon 8 of 9	ENSP00000423706.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45187 AN: 151540 Hom.: 6783 Cov.: 31

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.286 AC: 64441 AN: 225264 AF XY: 0.289

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.292 AC: 396569 AN: 1358250 Hom.: 59333 Cov.: 24 AF XY: 0.293 AC XY: 198605 AN XY: 677786

African (AFR) AF: 0.283 AC: 8583 AN: 30318

American (AMR) AF: 0.245 AC: 9102 AN: 37172

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7210 AN: 24702

East Asian (EAS) AF: 0.175 AC: 6811 AN: 38930

South Asian (SAS) AF: 0.296 AC: 22446 AN: 75886

European-Finnish (FIN) AF: 0.296 AC: 15575 AN: 52654

Middle Eastern (MID) AF: 0.316 AC: 1708 AN: 5410

European-Non Finnish (NFE) AF: 0.298 AC: 308564 AN: 1036346

Other (OTH) AF: 0.292 AC: 16570 AN: 56832

GnomAD4 genome AF: 0.298 AC: 45211 AN: 151658 Hom.: 6791 Cov.: 31 AF XY: 0.294 AC XY: 21781 AN XY: 74070

African (AFR) AF: 0.301 AC: 12416 AN: 41288

American (AMR) AF: 0.271 AC: 4129 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3466

East Asian (EAS) AF: 0.168 AC: 867 AN: 5164

South Asian (SAS) AF: 0.283 AC: 1360 AN: 4812

European-Finnish (FIN) AF: 0.299 AC: 3122 AN: 10456

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21187 AN: 67930

Other (OTH) AF: 0.300 AC: 632 AN: 2104

Alfa AF: 0.307 Hom.: 18448

Bravo AF: 0.298

Asia WGS AF: 0.218 AC: 757 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Asphyxiating thoracic dystrophy 5 (2)
-	-	2	Cranioectodermal dysplasia 4 (2)
-	-	2	not provided (2)
-	-	1	Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 (1)
-	-	1	Nephronophthisis 13 (1)
-	-	1	Senior-Loken syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		1.5
Mutation Taster		=64/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.022
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: rs2167494; hg19: chr4-39216221; COSMIC: COSV56464666; COSMIC: COSV56464666;