rs17584431

Variant names:

• chr4-39205698-A-G
• rs17584431
• NM_025132.4:c.852A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025132.4(WDR19):​c.852A>G​(p.Ser284Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,608,074 control chromosomes in the GnomAD database, including 19,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1330 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18452 hom.)
• Consequence: WDR19 NM_025132.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.250
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 4-39205698-A-G is Benign according to our data. Variant chr4-39205698-A-G is described in ClinVar as Benign. ClinVar VariationId is 261866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 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.852A>G	p.Ser284Ser	synonymous	Exon 9 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.372A>G	p.Ser124Ser	synonymous	Exon 8 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.852A>G	p.Ser284Ser	synonymous	Exon 9 of 37	ENSP00000382717.3
	WDR19	ENST00000503697.5	TSL:1	n.*320A>G		non_coding_transcript_exon	Exon 7 of 9	ENSP00000423706.1
	WDR19	ENST00000503697.5	TSL:1	n.*320A>G		3_prime_UTR	Exon 7 of 9	ENSP00000423706.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18279 AN: 152088 Hom.: 1328 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.158 AC: 37919 AN: 239844 AF XY: 0.164

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.155 AC: 226237 AN: 1455868 Hom.: 18452 Cov.: 32 AF XY: 0.158 AC XY: 114513 AN XY: 723626

African (AFR) AF: 0.0250 AC: 835 AN: 33440

American (AMR) AF: 0.168 AC: 7341 AN: 43766

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3208 AN: 26000

East Asian (EAS) AF: 0.166 AC: 6579 AN: 39594

South Asian (SAS) AF: 0.231 AC: 19687 AN: 85254

European-Finnish (FIN) AF: 0.172 AC: 9135 AN: 53110

Middle Eastern (MID) AF: 0.157 AC: 902 AN: 5758

European-Non Finnish (NFE) AF: 0.153 AC: 169402 AN: 1108746

Other (OTH) AF: 0.152 AC: 9148 AN: 60200

GnomAD4 genome AF: 0.120 AC: 18280 AN: 152206 Hom.: 1330 Cov.: 32 AF XY: 0.123 AC XY: 9182 AN XY: 74408

African (AFR) AF: 0.0287 AC: 1194 AN: 41554

American (AMR) AF: 0.149 AC: 2284 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3472

East Asian (EAS) AF: 0.154 AC: 797 AN: 5180

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4824

European-Finnish (FIN) AF: 0.172 AC: 1824 AN: 10576

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10266 AN: 68004

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.144 Hom.: 3674

Bravo AF: 0.115

Asia WGS AF: 0.168 AC: 584 AN: 3478

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	-0.51
CADD	Benign	8.3
DANN	Benign	0.67
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17584431; hg19: chr4-39207318; COSMIC: COSV56468473; COSMIC: COSV56468473;